Triazolo[4,5-D] pyramidine derivatives and their use as purine receptor antagonists

ABSTRACT

Compounds of formula (I) that are capable of acting as purine receptor antagonists, pharmaceutical compositions including the compounds, and methods of making the compounds, are disclosed. The compounds and compositions can be used in treating or preventing disorders related to purine receptor hyperfunctioning.

This application is a divisional of U.S. patent application Ser. No.15/682,346, filed Aug. 21, 2017, which is a divisional of U.S. patentapplication Ser. No. 15/172,126, filed Jun. 2, 2016, now U.S. Pat. No.9,765,080, which is a continuation of U.S. patent application Ser. No.14/618,829, filed Feb. 10, 2015, now U.S. Pat. No. 9,376,443, which is acontinuation of U.S. patent application Ser. No. 13/889,921, filed May8, 2013, now U.S. Pat. No. 8,987,279, which is a divisional of U.S.patent application Ser. No. 12/997,721, filed Mar. 31, 2011, now U.S.Pat. No. 8,450,328, which is the National Phase of International PatentApplication No. PCT/GB2009/001605, filed Jun. 25, 2009, which claimspriority from U.S. Provisional Patent Application No. 61/075,538, filedJun. 25, 2008, and Great Britain Patent Application No. 0906579.8, filedApr. 16, 2009. The contents of these applications are incorporatedherein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions andmethods, and methods of making and using the same.

BACKGROUND TO THE INVENTION

Movement disorders constitute a serious health problem, especially amongthe elderly. These movement disorders can often be the result of brainlesions. Disorders involving the basal ganglia which result in movementdisorders include Parkinson's disease, Huntington's chorea and Wilson'sdisease. Furthermore, dyskinesias often arise as sequelae of cerebralischaemia and other neurological disorders.

There are four classic symptoms of Parkinson's disease: tremor,rigidity, akinesia and postural changes. The disease is also commonlyassociated with depression, dementia and overall cognitive decline.Parkinson's disease has a prevalence of 1 per 1,000 of the totalpopulation. The incidence increases to 1 per 100 for those aged over 60years. Degeneration of dopaminergic neurons in the substantia nigra andthe subsequent reductions in interstitial concentrations of dopamine inthe striatum are critical to the development of Parkinson's disease.Some 80% of cells from the substantia nigra can be destroyed before theclinical symptoms of Parkinson's disease become apparent.

Some strategies for the treatment of Parkinson's disease are based ontransmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)),inhibition of monoamine oxidase (e.g., Deprenyl™), dopamine receptoragonists (e.g., bromocriptine and apomorphine) and anticholinergics(e.g., benztrophine, orphenadrine). Transmitter replacement therapy maynot provide consistent clinical benefit, especially after prolongedtreatment when “on-off” symptoms develop. Furthermore, such treatmentshave also been associated with involuntary movements of athetosis andchorea, nausea and vomiting. Additionally, current therapies do nottreat the underlying neurodegenerative disorder resulting in acontinuing cognitive decline in patients.

Blockade of A₂ adenosine receptors has been implicated in the treatmentof movement disorders such as Parkinson's disease, Restless legssyndrome, nocturnal myoclonus and in the treatment of cerebral ischemia.See, for example, WO 02/055083; Richardson, P. J. et al., TrendsPharmacol. Sci. 1997, 18, 338-344; and Gao, Y. and Phillis, J. W., LifeSci. 1994, 55, 61-65, each of which is incorporated by reference in itsentirety. Adenosine A_(2A) receptor antagonists have potential use inthe treatment of movement disorders such as Parkinson's Disease (Mally,J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320, which is incorporatedby reference in its entirety).

Adenosine is a naturally occurring purine nucleoside which has a widevariety of well-documented regulatory functions and physiologicaleffects. The central nervous system (CNS) effects of this endogenousnucleoside have attracted particular attention in drug discovery,because of the therapeutic potential of purinergic agents in CNSdisorders (Jacobson, K. A. et al., J. Med. Chem 1992, 35, 407-422, andBhagwhat, S. S.; Williams, M. E. Opin. Ther. Patents 1995, 5, 547-558,each which is incorporated by reference in its entirety).

Adenosine receptors represent a subclass (P₁) of the group of purinenucleotide and nucleoside receptors known as purinoreceptors. The mainpharmacologically distinct adenosine receptor subtypes are known as A₁,A_(2A), A_(2B) (of high and low affinity) and A₃ (Fredholm, B. B., etal., Pharmacol. Rev. 1994, 46, 143-156, which is incorporated byreference in its entirety). The adenosine receptors are present in theCNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128, which isincorporated by reference in its entirety).

P₁ receptor-mediated agents can be useful in the treatment of cerebralischemia or neurodegenerative disorders, such as Parkinson's disease(Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300;Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722; and Williams,M. and Bumnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26.Editor. Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-liss,New York, N.Y., which is incorporated by reference in its entirety).

It has been speculated that xanthine derivatives such as caffeine mayoffer a form of treatment for attention-deficit hyperactivity disorder(ADHD). A number of studies have demonstrated a beneficial effect ofcaffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al.,Psychiatry, 1981, 26, 395-401, which is incorporated by reference in itsentirety). Antagonism of adenosine receptors is thought to account forthe majority of the behavioral effects of caffeine in humans and thusblockade of adenosine A_(2A) receptors may account for the observedeffects of caffeine in ADHD patients. Therefore a selective adenosineA_(2A) receptor antagonist may provide an effective treatment for ADHDbut with decreased side-effects.

Adenosine receptors can play an important role in regulation of sleeppatterns, and indeed adenosine antagonists such as caffeine exert potentstimulant effects and can be used to prolong wakefulness(Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268, which isincorporated by reference in its entirety). Adenosine's sleep regulationcan be mediated by the adenosine A_(2A) receptor (Satoh, S., et al.,Proc. Natl. Acad. Sci., USA, 1996, 93: 5980-5984, which is incorporatedby reference in its entirety). Thus, a selective adenosine A_(2A)receptor antagonist may be of benefit in counteracting excessivesleepiness in sleep disorders such as hypersomnia or narcolepsy.

Patients with major depression demonstrate a blunted response toadenosine agonist-induced stimulation in platelets, suggesting that adysregulation of adenosine A_(2A) receptor function may occur duringdepression (Berk, M. et al., 2001, Eur. Neuropsycopharmacol. 11,183-186, which is incorporated by reference in its entirety).Experimental evidence in animal models has shown that blockade ofadenosine A_(2A) receptor function confers antidepressant activity (ElYacoubi, M et al., Br. J. Pharmacol 2001, 134, 68-77, which isincorporated by reference in its entirety). Thus, adenosine A_(2A)receptor antagonists may be useful in treatment of major depression andother affective disorders in patients.

The pharmacology of adenosine A_(2A) receptors has been reviewed(Ongini, E.; Fredholm, B. B. Trends Pharmacol Sci. 1996, 17(10),364-372, which is incorporated by reference in its entirety). Onepossible mechanism in the treatment of movement disorders by adenosineA_(2A) antagonists is that A_(2A) receptors may be functionally linkeddopamine D₂ receptors in the CNS. See, for example, Ferre, S. et al.,Proc. Natl. Acad. Sci. USA 1991, 88, 7238-7241; Puxe, K. et al.,Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., (Proc. Int.Symp.), 5th (1995), 499-507. Editors: Belardinelr, Luiz; Pelleg, Amir.Publisher: Kluwer, Boston, Mass.; and Ferre, S. et al., Trends Neurosci.1997, 20, 482-487, each of which is incorporated by reference in itsentirety.

Interest in the role of adenosine A_(2A) receptors in the CNS, due inpart to in vivo studies linking A_(2A) receptors with catalepsy (Ferreet al., Neurosci Lett. 1991, 130, 1624; and Mandhane, S. N. et al., Eur.J. Pharmacol 1997, 328, 135-141, each of which is incorporated byreference in its entirety), has prompted investigations into agents thatselectively bind to adenosine A_(2A) receptors.

One advantage of adenosine A_(2A) antagonist therapy is that theunderlying neurodegenerative disorder may also be treated. See, e.g.,Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N.Y. Acad. Sci.1997, 825 (Neuroprotective Agents), 3048, which is incorporated byreference in its entirety. In particular, blockade of adenosine A_(2A)receptor function confers neuroprotection against MPTP-inducedneurotoxicity in mice (Chen, J-F., J. Neurosci. 2001, 21, RC143, whichis incorporated by reference in its entirety). In addition, consumptionof dietary caffeine (a known adenosine A_(2A) receptor antagonist), isassociated with a reduced risk of Parkinson's disease (Ascherio, A. etal, Ann. Neurol., 2001, 50, 56-63; and Ross G. W., et al., JAMA, 2000,283, 2674-9, each of which is incorporated by reference in itsentirety). Thus, adenosine A_(2A) receptor antagonists may conferneuroprotection in neurodegenerative diseases such as Parkinson'sdisease.

Xanthine derivatives have been disclosed as adenosine A_(2A) receptorantagonists for treating various diseases caused by hyperfunctioning ofadenosine A₂ receptors, such as Parkinson's disease (see, for example,EP-A-565377, which is incorporated by reference in its entirety). Oneprominent xanthine-derived adenosine A_(2A) selective antagonist is CSC[8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323,141-144, which is incorporated by reference in its entirety).

Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is amixed antagonist at adenosine A₁ and A_(2A) receptors, has been studiedclinically. To determine whether a formulation of this adenosinereceptor antagonist would be of value in Parkinson's disease an opentrial was conducted on 15 Parkinsonian patients, treated for up to 12weeks with a slow release oral theophylline preparation (150 mg/day),yielding serum theophylline levels of 4.44 mg/L after one week. Thepatients exhibited significant improvements in mean objective disabilityscores and 11 reported moderate or marked subjective improvement (Mally,J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515-517, which isincorporated by reference in its entirety).

KF 17837 (E-8-(3,4dimethoxystyryl)-1,3-dipropyl-7-methylxanthine) is aselective adenosine A_(2A) receptor antagonist which on oraladministration significantly ameliorated the cataleptic responsesinduced by intracerebroventricular administration of an adenosine A_(2A)receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy inducedby haloperidol and reserpine. Moreover, KF 17837 potentiated theanticataleptic effects of a subthreshold dose of L-DOPA plusbenserazide, suggesting that KF 17837 is a centrally active adenosineA_(2A) receptor antagonist and that the dopaminergic function of thenigrostriatal pathway is potentiated by adenosine A_(2A) receptorantagonists (Kanda, T. et al., Eur. J. Pharmacol 1994, 256, 263-268,which is incorporated by reference in its entirety). The structureactivity relationship (SAR) of KF 17837 has been published (Shimada, J.et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352, which isincorporated by reference in its entirety). Recent data has also beenprovided on the adenosine A_(2A) receptor antagonist KW-6002 (Kuwana, Yet al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al.,Ann. Neurol. 1998, 43(4), 507-513, each of which is incorporated byreference in its entirety).

Non-xanthine structures sharing these pharmacological properties includeSCH 58261 and its derivatives (Baraldi, P. G. et al., J. Med Chem. 1996,39, 1164-71, which is incorporated by reference in its entirety). SCH58261(7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movementdisorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70, which isincorporated by reference in its entirety) and has been followed up by alater series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998,41(12), 2126-2133, which is incorporated by reference in its entirety).

Accordingly, blocking of purine receptors, particularly adenosinereceptors, and more particularly adenosine A_(2A) receptors may bebeneficial in treatment or prevention of movement disorders such asParkinson's disease, Restless leg syndrome and nocturnal myoclonus, ordisorders such as depression, cognitive, or memory impairment, acute andchronic pain, ADHD or narcolepsy, or for neuroprotection in a subject.

A number of adenosine A_(2A) antagonists are described in InternationalPatent Application Publication WO 02/055083 A1, which is incorporated byreference in its entirety.

DESCRIPTION OF THE INVENTION

The compounds of the present invention are selective adenosine A_(2A)antagonists. Thus, they have particular affinity for the adenosineA_(2A) receptor and demonstrate selectivity for this receptor over theother types of adenosine receptors (A₁, A_(2B), A₃). Significantly, thecompounds of the present invention show greater selectivity for theadenosine A_(2A) receptor than for the adenosine A_(2B) receptor whencompared to known adenosine A_(2A) receptor antagonists. Selectivityover the adenosine A_(2B) receptor is advantageous for the reasonsdiscussed below.

The adenosine A_(2B) receptor is highly abundant in bone marrowmacrophages and vascular smooth muscle. A_(2B) receptor knockout studieshave demonstrated that removal of the A_(2B) receptor in mice produces ahigher level of vascular injury following femoral artery injury thanseen in wild-type mice, the signal for which originates from bone marrowcells (Yang et al., 2008). Vascular injury represents a criticalinitiating event in the pathogenesis of various vascular diseases,including atherosclerosis, restenosis and sepsis. It is therefore likelythat sustained antagonism of adenosine A_(2B) receptors increases thelikelihood of vascular injury, and provokes the onset of variousvascular diseases. A high degree of selectivity for antagonism ofadenosine A_(2A) versus A_(2B) receptors is therefore a highly desirablefeature, especially in an anti-Parkinson's treatment, the target diseasepopulation for which is likely to be elderly and at risk of developingvascular disease heart disease (Yang D, Koupenova M, McCrann D J,Kopeikina K J, Kagan H M, Schreiber B M, and Ravid K (2008) “The A2badenosine receptor protects against vascular injury”, Proc. Natl. AcadSci. 105(2): 792-796).

As previously mentioned, the compounds of the present invention alsoshow greater selectivity for the adenosine A_(2A) receptor than for theadenosine A₃ receptor. Again, this selectivity has significant benefits,as discussed below.

Adenosine released during cardiac ischemia exerts a potent, protectiveeffect in the heart. There is strong evidence that activation ofadenosine A₃ receptors plays a large part in mediating this protection(Liang and Jacobson, 1998). It is likely therefore that sustainedblockade of adenosine A₃ receptors might increase the likelihood ofcomplications resulting from any pre-existing or developing ischaemicheart disease, such as angina or heart failure. A high degree ofselectivity for antagonism of adenosine A_(2A) versus A₃ receptors istherefore a highly desirable feature, especially in an anti-Parkinson'streatment, the target disease population for which is likely to beelderly and at risk of ischaemic heart disease (Liang B T and Jacobson KA (1998). A physiological role of the adenosine A3 receptor: Sustainedcardioprotection. Proc. Natl. Acad. Sci. 95 (12): 6995-9).

In an aspect, the present invention provides compounds of formula (I):

wherein:R¹ is phenyl or heteroaryl, wherein said phenyl or said heteroaryl groupmay be optionally substituted with alkyl, alkoxy, halo or —CN;R^(a) is H or alkyl;R^(b) is H or alkyl;or R^(a) and R^(b) together with the atom to which they are attachedform a 3 to 8 membered saturated or partially saturated hydrocarbon ringor form a 4 to 8 membered saturated or partially saturated heterocylicring comprising a ring member selected from O, N(R³) and S;R² is H, alkyl or heterocycloalkyl, wherein said alkyl may optionally besubstituted with halo, alkoxy or heterocycloalkyl;provided that R² is selected from heterocycloalkyl and alkyl substitutedby halo, alkoxy or heterocycloalkyl, when R¹ is furan-2-yl or5-methyl-furan-2-yl and R^(a) and R^(b) are both H;R³ is H or alkyl;wherein:

heteroaryl is a 5 or 6 membered aromatic ring, comprising one or tworing members selected from N, N(R⁴), S and O;

alkyl (or the alkyl group of the alkoxy group) is a linear or branchedsaturated hydrocarbon containing up to 10 carbon atoms;

heterocycloalkyl is a C-linked or N-linked 3 to 10 memberednon-aromatic, monocyclic ring, wherein said heterocycloalkyl ringcomprises 1, 2 or 3 ring members independently selected from N, N(R⁴),S(O)_(q) and O;

R⁴ is H or alkyl;

q is 0, 1 or 2;

and tautomers, stereoisomers, pharmaceutically acceptable salts andsolvates thereof.

In an aspect the present invention provides a prodrug of a compound offormula (I) as herein defined, or a pharmaceutically acceptable saltthereof.

In an aspect the present invention provides an N-oxide of a compound offormula (I) as herein defined, or a prodrug or pharmaceuticallyacceptable salt thereof.

It will be understood that certain compounds of the present inventionmay exist in solvated, for example hydrated, as well as unsolvatedforms. It is to be understood that the present invention encompasses allsuch solvated forms.

In an aspect, the present invention provides a pharmaceuticalcomposition includes a pharmaceutically acceptable carrier and acompound of formula (I) as defined above, or a pharmaceuticallyacceptable salt or solvate thereof.

In an aspect, the present invention provides a method of treating adisorder comprising administering an effective dose of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,to a subject in need of treatment of a disorder treatable by purinereceptor blocking.

In an aspect, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, for use in thetreatment of a disorder treatable by purine receptor blocking.

In an aspect, the present invention provides for the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for the treatment of adisorder treatable by purine receptor blocking.

The disorder can be related to hyper functioning of purine receptors.The subject can be in need of adenosine receptor blocking. The purinereceptors can be adenosine A_(2A) receptors. The disorder can be amovement disorder. The movement disorder can be Parkinson's disease,Restless legs syndrome or nocturnal myoclonus; or the movement disordercan be drug-induced Parkinsonism, post-encephalitic Parkinsonism,Parkinsonism induced by poisoning or post-traumatic Parkinson's disease.The movement disorder can be progressive supernuclear palsy,Huntington's disease, multiple system atrophy, corticobasaldegeneration, Wilson's disease, Hallerrorden-Spatz disease, progressivepallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity orother disorders of the basal ganglia which result in dyskinesias.

The treatment can include administering to the subject an additionaldrug useful in the treatment of movement disorders. The additional druguseful in the treatment of movement disorders can be a drug useful inthe treatment of Parkinson's disease, such as, for example, L-DOPA or adopamine agonist. The disorder can be depression, a cognitive or memoryimpairment disorder, acute or chronic pain, ADHD or narcolepsy. Thecognitive or memory impairment disorder can be Alzheimer's disease.

In an aspect, the present invention provides subset of the compounds offormula (I), wherein:

R¹ is selected from the group consisting of 5-methyl-furan-2-yl, phenyland 4-methylthiazol-2-yl;

R^(a) is H or alkyl;

R^(b) is H or alkyl;

or R^(a) and R^(b) together with the atom to which they are attachedform a 4 to 6 membered saturated hydrocarbon ring or form a 5 or 6membered saturated heterocyclic ring comprising a ring member selectedfrom O, N(R³) and S;

R² is H, alkyl, alkoxyalkyl- or heterocycloalkyl;

provided that R² is H, alkoxyalkyl- or heterocycloalkyl when R¹ is5-methyl-furan-2-yl and R^(a) and R^(b) are both H;

R³ is H or alkyl;

wherein heteroaryl, alkyl (or the alkyl group of the alkoxy oralkoxyalkyl group) and heterocycloalkyl are as previously defined;

and tautomers, stereoisomers, pharmaceutically acceptable salts andsolvates thereof.

The present invention also comprises the following aspects andcombinations thereof:

In an aspect, the present invention provides a compound of formula (I)wherein R¹ is selected from phenyl and heteroaryl, wherein said phenylor said heteroaryl may be optionally substituted with alkyl or alkoxy.

In an aspect, the present invention provides a compound of formula (I)wherein R¹ is selected from phenyl, thienyl, furanyl, pyrrolyl,pyrazolyl, imidazoyl, oxazolyl, isoxazolyl and thiazolyl, wherein eachmay be optionally substituted with alkyl or alkoxy.

In an aspect, the present invention provides a compound of formula (I)wherein R¹ is selected from phenyl, 2-furanyl, 2-pyrrolyl, 2-imidazoyl,2-oxazolyl, and 2-thiazolyl, wherein each may be optionally substitutedwith alkyl or alkoxy.

In an aspect, the present invention provides a compound of formula (I)wherein R¹ is selected from 5-methyl-furan-2-yl, phenyl and4-methylthiazol-2-yl.

In an aspect, the present invention provides a compound of formula (I)wherein R¹ is 5-methyl-furan-2-yl.

In an aspect, the present invention provides a compound of formula (I)wherein R^(a) and R^(b) together with the atom to which they areattached form a 4 to 6 membered saturated hydrocarbon ring or form a 5or 6 membered saturated heterocylic ring comprising a ring memberselected from O and N(R³); wherein R³ is as previously defined.

In an aspect, the present invention provides a compound of formula (I)wherein R^(a) and R^(b) together with the atom to which they areattached form a tetrahydropyryl ring, a cyclobutyl ring, a cyclopentylring or a cyclohexyl ring.

In an aspect, the present invention provides a compound of formula (I)wherein R^(a) and R^(b) are independently selected from H and(C₁-C₆)alkyl.

In an aspect, the present invention provides a compound of formula (I)wherein R^(a) and R^(b) are independently selected from H and methyl.

In an aspect, the present invention provides a compound of formula (I)wherein R^(a) and R^(b) are both H.

In an aspect, the present invention provides a compound of formula (I)wherein R² is selected from H, (C₁-C₆)alkyl and heterocycloalkyl,wherein said (C₁-C₆)alkyl may optionally be substituted with fluoro,(C₁-C₆)alkoxy, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl andpiperidinyl.

In an aspect, the present invention provides a compound of formula (I)wherein R² is selected from H, (C₁-C₄)alkyl and tetrahydrofuranyl,wherein said (C₁-C₄)alkyl may optionally be substituted with fluoro,(C₁-C3)alkoxy and tetrahydrofuranyl.

In an aspect, the present invention provides a compound of formula (I)wherein R² is selected from H and tetrahydrofuranyl.

In an aspect, heteroaryl is a 5 membered aromatic ring, containing oneor two N atoms, or one N atom and one NR⁴ atom, or one NR⁴ atom and oneS or one O atom; wherein R⁴ is as previously defined.

In an aspect, heterocycloalkyl is a C-linked 5 or 6 memberednon-aromatic, monocyclic ring, wherein said ring comprises 1 or 2 ringmembers independently selected from NR⁴ and O; wherein R⁴ is aspreviously defined.

In an aspect, the present invention provides a compound of formula (I)selected from:

7-(5-methylfuran-2-yl)-3-(6-[2-isopropyloxyethyoxy]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

S-7-phenyl-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-phenyl-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-phenyl-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-phenyl-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-phenyl-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

S-7-(3-methoxyphenyl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

S-7-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-methoxyphenyl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-methoxyphenyl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-methoxyphenyl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-methoxyphenyl)-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-cyclohexyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

S-7-(3-cyanophenyl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-cyanophenyl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-cyanophenyl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-cyanophenyl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-methoxyphenyl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(3-cyanophenyl)-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

S-7-(4-methylthiazol-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[difluoromethyloxymethyl]-pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-phenyl-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[2-ethoxyethoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-2-ylmethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-3-ylmethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[1-methoxy-1-methylethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(5-methylfuran-2-yl)-3-(6-[2,2,2-trifluoroethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

S-7-(thiazol-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

7-(4-methylthiazol-2-yl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine;

and pharmaceutically acceptable salts and solvates thereof.

The skilled person will appreciate that each of the compounds identifiedabove, or identified in the Examples provided herein below, taken aloneor with any combination of the other identified compounds represents anindependent aspect of the invention.

Definitions:

The term “alkyl” is as previously defined and denotes saturatedhydrocarbon residues including:

-   -   linear groups up to 10 atoms (C₁-C₁₀), or of up to 6 atoms        (C₁-C₆), or of up to 4 atoms (C₁-C₄). Examples of such alkyl        groups include, but are not limited, to C₁—methyl, C₂—ethyl,        C₃—propyl and C₄—n-butyl.    -   branched groups of between 3 and 10 atoms (C₃-C₁₀), or of up to        7 atoms (C₃-C₇), or of up to 4 atoms (C₃-C₄). Examples of such        alkyl groups include, but are not limited to, C3—iso-propyl,        C₄—sec-butyl, C₄—iso-butyl, C₄—tert-butyl and C₅—neo-pentyl.

The term “alkoxy” denotes O-linked hydrocarbon residues including:

-   -   linear groups of between 1 and 6 atoms (C₁-C₆), or of between 1        and 4 atoms (C₁-C₄). Examples of such alkoxy groups include, but        are not limited to, C₁—methoxy, C₂—ethoxy, C₃—n-propoxy and        C₄—n-butoxy.    -   branched groups of between 3 and 6 atoms (C₃-C₆) or of between 3        and 4 atoms (C₃-C₄). Examples of such alkoxy groups include, but        are not limited to, C₃—iso-propoxy, and C₄—sec-butoxy and        tert-butoxy.

The term “alkoxyalkyl-” denotes an alkyl-O-alkyl- group in which alkylis as described below. Examples of suitable alkoxyalkyl- groups include,but are not limited to, methoxymethyl (CH₃OCH₂—) and ethoxymethyl(C₂H₅OCH₂—).

The term “halo” denotes a halogen atom selected from Cl, F, Br and I.

The term “heterocycloalkyl” is as defined above. Examples of suitableheterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl,thiomorpholinyl-1-oxide, thiomorpholinyl-1,1-dioxide, piperazinyl,N-methylpiperazinyl, azepinyl oxazepinyl, diazepinyl, and1,2,3,4-tetrahydropyridinyl.

The term “heteroaryl” is as defined above. Examples of suitableheteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl,imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,pyridazinyl, pyrimidinyl and pyrazinyl.

The term “C-linked”, such as in “C-linked heterocycloalkyl”, means thatthe heterocycloalkyl group is joined to the remainder of molecule via aring carbon atom.

The term “N-linked”, such as in “N-linked heterocycloalkyl”, means thatthe heterocycloalkyl group is joined to the remainder of the moleculevia a ring nitrogen atom.

The term “O-linked”, such as in “O-linked hydrocarbon residue”, meansthat the hydrocarbon residue is joined to the remainder of the moleculevia an oxygen atom.

In groups such as “alkoxyalkyl-” and “—CN”, the symbol denotes the pointof attachment of the group to the remainder of the molecule.

“Pharmaceutically acceptable salt” means a physiologically ortoxicologically tolerable salt and includes, when appropriate,pharmaceutically acceptable base addition salts and pharmaceuticallyacceptable acid addition salts. Hemisalts of acids and bases can also beformed, for example, hemisulfate and hemicalcium salts. For a review ofsuitable salts, see “Handbook of Pharmaceutical Salts: Properties,Selection and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002).

“Prodrug” refers to a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound of theinvention. Suitable groups for forming pro-drugs are described in ‘ThePractice of Medicinal Chemistry, 2^(nd) Ed. pp 561-585 (2003) and in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.

The compounds of the invention can exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when the solvent is water.

Where compounds of the invention exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includinghut not limited to cis- -and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms. Unless otherwise stated a referenceto a particular compound includes all such isomeric forms, includingracemic and other mixtures thereof. Where appropriate such isomers canbe separated from their mixtures by the application or adaptation ofknown methods (e.g. chromatographic techniques and recrystallisationtechniques). Where appropriate such isomers can be prepared by theapplication or adaptation of known methods (e.g. asymmetric synthesis).

For example, the use of certain combinations of substituents R^(a) andR^(b) can generate chiral compounds of the present invention such as:

Similarly, the use of certain R² substituents can generate chiralcompounds of the present invention such as:

In the context of the present invention, references herein to“treatment” include references to curative, palliative and prophylactictreatment.

Therapeutic Applications

The compounds of the present invention are useful as purine receptorantagonists, for example, as adenosine A_(2A) antagonists.

Pharmaceutically acceptable salts of the compounds of the presentinvention are also suitable as purine receptor antagonists, for example,as adenosine A_(2A) antagonists.

The compounds of the present invention can be used for treating orpreventing a disorder in which the blocking of purine receptors,particularly adenosine receptors and more particularly adenosine A_(2A)receptors, may be beneficial. The compounds can be administered to asubject in need of such treatment. For example, an effective dose of acompound of formula (I) or a pharmaceutically acceptable salt or prodrugthereof can be administered to a subject. The disorder may be caused bythe hyperfunctioning of the purine receptors.

Disorders of particular interest include those in which the blocking ofpurine receptors, particularly adenosine receptors and more particularlyadenosine A_(2A) receptors, may be beneficial. These include movementdisorders such as Parkinson's disease, drug-induced Parkinsonism,post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (forexample MIP, manganese, carbon monoxide) and post-traumatic Parkinson'sdisease (punch-drunk syndrome).

Other movement disorders in which the blocking of purine receptors, maybe of benefit include progressive supranuclear palsy, Huntingtonsdisease, multiple system atrophy, corticobasal degeneration, Wilsonsdisease, Hallerrorden-Spatz disease, progressive pallidal atrophy,Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders ofthe basal ganglia which result in abnormal movement or posture. Thepresent invention may also be effective in treating Parkinson's withon-off phenomena; Parkinson's with freezing (end of dose deterioration);and Parkinson's with prominent dyskinesias.

The compounds of formula (I) may be used or administered in combinationwith one or more additional drugs useful in the treatment of movementdisorders, such as L-DOPA or a dopamine agonist, the components being inthe same formulation or in separate formulations for administrationsimultaneously or sequentially.

Other disorders in which the blocking of purine receptors, particularlyadenosine receptors and more particularly adenosine A_(2A) receptors maybe beneficial include acute and chronic pain; for example neuropathicpain, cancer pain, trigeminal neuralgia, migraine and other conditionsassociated with cephalic pain, primary and secondary hyperalgesia,inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain,spinal cord injury pain, central pain, post-herpetic pain and HIV pain;affective disorders including mood disorders such as bipolar disorder,seasonal affective disorder, depression, manic depression, atypicaldepression and monodepressive disease; central and peripheral nervoussystem degenerative disorders including corticobasal degeneration,demyelinating disease (multiple sclerosis, disseminated sclerosis),Friedrich's ataxia, motoneuron disease (amyotrophic lateral sclerosis,progressive bulbar atrophy), multiple system atrophy, myelopathy,radiculopathy, peripheral neuropathy (diabetic neuropathy, tabesdorsalis, drug induced neuropathy, vitamin deficiency), systemic lupuserythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy,progressive pallidal atrophy, progressive supranuclear palsy,spasticity; schizophrenia and related psychoses; cognitive disordersincluding dementia, Alzheimer's Disease, Frontotemporal dementia,multi-infarct dementia, AIDS dementia, dementia associated withHuntington's Disease, Lewy body dementia, senile dementia, age-relatedmemory impairment, cognitive impairment associated with dementia,Korsakoff syndrome, dementia pugilans; attention disorders such asattention-deficit hyperactivity disorder (ADHD), attention deficitdisorder, minimal brain dysfunction, brain-injured child syndrome,hyperkinetic reaction childhood, and hyperactive child syndrome; centralnervous system injury including traumatic brain injury, neurosurgery(surgical trauma), neuroprotection for head injury, raised intracranialpressure, cerebral edema, hydrocephalus, spinal cord injury; cerebralischemia including transient ischemic attack, stroke (thrombotic stroke,ischemic stroke, embolic stroke, hemorrhagic stroke, lacunar stroke)subarachnoid hemorrhage, cerebral vasospasm, neuroprotection for stroke,peri-natal asphyxia, drowning, cardiac arrest, subdural hematoma;myocardial ischemia; muscle ischemia; sleep disorders such ashypersomnia and narcolepsy; eye disorders such as retinalischemia-reperfusion injury and diabetic neuropathy; cardiovasculardisorders such as claudication and hypotension; and diabetes and itscomplications.

Synthetic Methods

Compounds of formula (I) may be prepared according to conventionalsynthetic methods. For example compounds of formula (I) may besynthesized by methods such as those illustrated in Reaction Scheme 1.In this scheme R represents —(CR^(a)R^(b))—O—R².

Compounds of formula (4) may be-prepared from compounds of formula (3)by standard methods such as reaction with an appropriate alkyl halide,or substituted alkyl halide (e.g., an arylalkyl halide) in the presenceof a suitable base such as sodium hydride.

Compounds of formula (3) may be prepared from the known chloro compoundof formula (2) by standard methods such as phenyl or heteroaryl couplingreactions. Suitable phenyl or heteroaryl coupling reactions wouldinclude reaction with an appropriate phenyl- or heteroaryl-boronic acidderivative, an phenyl- or heteroaryl-trialkylstannane derivative or anphenyl- or heteroaryl-zinc halide derivative in the presence of asuitable catalyst such as a palladium complex.

Compounds of formula (3) may also be prepared from compounds of formula(7) by standard methods such as treatment with isoamyl nitrite or sodiumnitrite. Compounds of formula (7) are either known in the literature orcan be prepared from compounds of formula (6) by standard methods suchas reduction with hydrogen in the presence of a suitable catalyst suchas Pd. Compounds of formula (6) are either known in the literature orcan be prepared from the known compound of formula (5) by standardmethods such as phenyl or heteroaryl coupling reactions as describedabove.

Compounds of formula (I) may also be synthesized by standard methodssuch as those illustrated in Reaction Scheme 2. In this scheme Rrepresents —(CR^(a)R^(b))—O—R².

Compounds of formula (4) may be prepared from compounds of formula (10)by standard methods such as phenyl or heteroaryl coupling reactions asdescribed above. Compounds of formula (10) can be prepared by methodsanalogous to those described in the literature. For example compounds offormula (10) may be prepared from compounds of formula (9) by standardmethods such as treatment with isoamyl nitrite or sodium nitrite.Compounds of formula (9) can be prepared by methods described in theliterature such as the treatment of the compound of formula (8) with anappropriate amine in a suitable solvent at elevated temperature.

Compounds of formula (10) can also be prepared by a modified version ofReaction Scheme 2, in which the 5-amino group of compound (8) isprotected, as shown in Reaction Scheme 2A. In this scheme R represents—(CR^(a)R^(b))—O—R² and PG represents a protecting group.

Compounds of formula (10) can be prepared from compounds of formula (9A)by standard methods such as treatment with isoamyl nitrite or sodiumnitrite. Compounds of formula (9A) can be prepared by methods such asthe treatment of the compound of formula (8A) with an appropriate aminein a suitable solvent at elevated temperature.

Compounds of formula (I) may also be synthesized by standard methodssuch as those illustrated in Reaction Scheme 3. In this scheme Rrepresents —(CR^(a)R^(b))—O—R².

Compounds of formula (4) can be prepared from compounds of formula (15)by standard methods such as treatment with isoamyl nitrite. Compounds offormula (15) may be prepared from compounds of formula (14) by standardmethods such as reduction with hydrogen in the presence of a suitablecatalyst such as Pd. Compounds of formula (14) may be prepared fromcompounds of formula (13), where X is a suitable leaving group such as atosylate or triflate group, by standard methods such as treatment with asuitable amine in the presence of a suitable base such as triethylamine.Compounds of formula (13) where X is a suitable leaving group are eitherknown in the literature or may be prepared from compounds of formula(12) by standard methods such as treatment with tosyl chloride ortriflic anhydride in the presence of a suitable base such astriethylamine or 2,6-dimethylpyridine. Compounds of formula (12) areeither known in the literature or may be prepared from the knowncompound of formula (11) by standard methods such as phenyl orheteroaryl coupling reactions as described above.

Compounds of formula (I) can be used in the form of pharmaceuticallyacceptable salts derived from inorganic or organic acids and bases.Included among such acid salts are the following: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups can be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides, such as benzyl andphenethyl bromides and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

The compound may be formulated into pharmaceutical compositions that maybe administered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques.

Pharmaceutical compositions can include a compound of formula (I), orpharmaceutically acceptable derivatives thereof, together with anypharmaceutically acceptable carrier. The term “carrier” as used hereinincludes acceptable adjuvants and vehicles. Pharmaceutically acceptablecarriers that may be used in the pharmaceutical compositions of thisinvention include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agentsand suspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as do natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions can be orally administered in any orallyacceptable dosage form including, but not limited to, capsules, tablets,aqueous suspensions or solutions.

In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried com starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions may be administered inthe form of suppositories for rectal administration. These can beprepared by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature but liquid at the rectal temperatureand therefore will melt in the rectum to release the drug. Suchmaterials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions may also be administered topically,especially when the target of treatment includes areas or organs readilyaccessible by topical application, including diseases of the eye, theskin, or the lower intestinal tract. Suitable topical formulations arereadily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions may also be administered by nasalaerosol or inhalation through the use of a nebulizer, a dry powderinhaler or a metered dose inhaler. Such compositions are preparedaccording to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated, and the particular mode of administration. It should beunderstood, however, that a specific dosage and treatment regimen forany particular patient will depend upon a variety of factors, includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the judgment of the treating physician and theseverity of the particular disease being treated. The amount of activeingredient may also depend upon the therapeutic or prophylactic agent,if any, with which the ingredient is co-administered.

A pharmaceutical composition can include an effective amount of acompound of formula (I). An effective amount is defined as the amountwhich is required to confer a therapeutic effect on the treated patient,and will depend on a variety of factors, such as the nature of theinhibitor, the size of the patient, the goal of the treatment, thenature of the pathology to be treated, the specific pharmaceuticalcomposition used, and the judgment of the treating physician. Forreference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219and Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.Dosage levels of between about 0.001 and about 100 mg/kg body weight perday, preferably between about 0.1 and about 10 mg/kg body weight per dayof the active ingredient compound are useful.

The following examples are for the purpose of illustration only and arenot intended to be limiting.

EXAMPLES Example 1S-7-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-Amino-6-chloro-5-nitro-4-pyrimidinol

250 mL (5 volumes) of concentrated sulfuric acid was stirred in a 1000mL round bottom flask (22° C.). To this, 2-amino-6-chloro-4-pyrimidinol(50 g) was added in portions. The temperature increased rapidly withearly additions, stabilizing at a temperature of 40° C. Later additionshad less effect on the temperature, a maximum of approx. 45° C. beingrecorded. Prior to addition of fuming nitric acid (45 mL, 0.9 volumes),the mixture was cooled (using an ice bath) to 20° C. In portions ofroughly 1.5 mL (reflecting pipette volume), nitric acid was addeddropwise at a steady rate (ca. 1 min between each portion). Earlyportions had the greatest effect on the temperature, the controlledexotherms reaching a temperature of approx. 26° C. before returning to20° C. under the influence of the ice bath. Later portions had littleeffect, and the temperature was maintained at approx. 21° C. After 45 mLof fuming nitric acid had been added in this way, the mixture wasallowed to stir for 2 hr (during this period the ice bath was removedand the temperature stabilised at room temperature ca. 22° C.). Theentire mixture was poured onto stirred ice/water (1200 mL) and theresulting yellow solid filtered under vacuum. The product was washed insuccession with water (600 mL), ethanol (600 mL) and diethylether (600mL). This method gave 63.5 g (98% yield) of the requirednitro-pyrimidinol.

2-Amino-6-(5-methyl-2-furyl)-5-nitro-4-pyrimidinol (12)

A biphasic solvent mixture of 1100 mL (22 volumes) tetrahydrofuran and550 mL (11 volumes) of aqueous sodium carbonate solution was stirred at22° C. in a 3000 mL three-necked round-bottomed flask. To this,2-amino-6-chloro-5-nitro-4-pyrimidinol (11) was added portionwise. Theresulting yellow solution was treated with a solution of5-methylfuran-2-boronic acid in ca. 30 mL THF (0.43 mol, 2 eq2-methylfuran initially). Tetrakis(triphenylphosphine)palladium (0) (5%,0.0072 moles, 8.32 g) was added and the reaction mixture heated to atemperature of 70° C. for 3 hr. The reaction mixture was cooled to 22°C. A small amount of turbidity was apparent at this point. The entiremixture was filtered and the filtrate reduced in vacuo to remove thetetrahydrofuran phase, leaving behind the alkaline aqueous phase. 1000mL (20 volumes) ethyl acetate was added and the mixture stirredvigorously for 15 min (this step serves to wash out neutralcontaminants, particularly triphenylphosphine oxide). The aqueous andorganic phases were separated and the organic phase back-extracted withaqueous sodium carbonate (800 mL). The combined aqueous phase was cooledusing an ice-bath and acidified (through drop-wise addition of HCl) topH 7. The resulting bright yellow precipitate was filtered under vacuum,washed with water and dried at 40° C. This method gave 37.8 g (67%) ofthe required product.

5-Methylfuran-2-Boronic Acid

1000 mL (25 volumes) of anhydrous tetrahydrofuran was stirred at 22° C.under a nitrogen atmosphere in a 2000 mL three-necked flask. 41.16 mL(0.43 mol) 2-methylfuran was added followed by 65 mL (0.43 mol, 1 eq)N,N,N′,N′-tetramethylethylenediamine. The solution was cooled to −78° C.and treated dropwise with n-butyllithium (1 eq, 172 mL, 2.5 M solutionin hexanes). The solution was stirred at −78° C. for a further 15 minbefore being slowly warmed to 22° C. Before dropwise addition oftrimethylborate (2 eq, 0.86 mol, 96.4 mL), the solution was re-cooled to−78° C. Again, the solution was allowed to slowly warm to 22° C.Hydrolysis of the newly formed boronic ester was achieved through theaddition of methanol:water (9:1, 280 mL). After 15 min the entiresolution was reduced in vacuo to leave a yellow/white solid. To ensurecomplete hydrolysis, the solid was taken up in further methanol (100 mL)and reduced in vacuo four times, eventually leaving a dark orange cruderesidue. This residue was taken up in ca. 30 mL THF and used directly inthe Suzuki coupling detailed above—the initial amount of 2-methylfuranused corresponds to 2 eq of the pyrimidinol starting material.

4-(5-Methyl-2-furyl)-5-nitro-6-(p-toluenesulphonyloxy)pyrimidine-2-amine(13)

A stirred suspension of2-amino-6-(5-methyl-2-furyl)-5-nitro-4-pyrimidinol (12) (20.96 g, 0.089mol) in dry acetonitrile (800 mL, 40 volumes) in a flame-driedthree-necked flask at 22° C. was treated with triethylamine (27.24 mL,0.196 mol, 2.2 eq). The resulting triethylamine salt was clearlyinsoluble in the reaction solvent, a thick yellow precipitate becomingapparent. The mixture was heated to a temperature of 50° C. and treatedportionwise with para-toluenesulfonyl chloride (18.57 g, 0.097 mol, 1.1eq). The yellow precipitate was rapidly replaced by a dark orange/brownsolution. Stirring at 50° C. was continued for a further 3.5 hr, afterwhich time LC-MS and TLC (1:1 EtOAc:iso-hexane) analysis indicated acomplete reaction. The reaction mixture was cooled to 22° C. and reducedin vacuo to yield a light brown solid. This was dissolved indichloromethane (800 mL, 40 volumes) and washed twice with 1.2-M aqueoushydrochloric acid. The organic fraction was dried over magnesium sulfateand reduced in vacuo to yield a cream coloured solid. Trituration withtoluene was effective in removing excess tosyl chloride to give therequired tosylate product (compound 13) as an off-white solid. Drying at40° C. left 22.33 g (65% yield).

(S)-{6-(Tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethylamino}-4-(5-methyl-2-furyl)-5-nitropyrimidine-2-amine

A stirred solution of4-(5-methyl-2-furyl)-5-nitro-6-(p-toluenesulphonyloxy)pyrimidine-2-amine(13) (26.3 g, 0.067 mol) in dry dimethoxyethane (1100 mL, 40 volumes) ina sealed, flame-dried, three-necked flask was treated with a solution ofthe (S)-6-(tetrahydrofuran-3-yloxymethyl)-2-pyridinemethanamine in dryDME (16.72 g, 0.080 mol, 1.2 eq). This solution was subsequently treatedwith triethylamine (27.96 mL, 0.201 mol, 3 eq) and warmed to atemperature of 50° C. After 18 hr, LC-MS analysis indicated the reactionto be ca. 90% complete (TLC (1:1 EtOAc:iso-hexane) indicated residualstarting material—further triethylamine addition and longer reactiontime did not drive the reaction any further). The reaction mixture wascooled to 22° C. and poured onto 1.25 M HCl (aq) (1200 mL). To this,ethyl acetate (1000 mL) was added and the mixture stirred vigorously for15 min. The aqueous phase was separated and neutralised using 2 Maqueous sodium carbonate solution. The resulting bright yellowprecipitate was filtered, washed with water and dried at 40° C. Thismethod gave 24.61 g (86% yield) of the required product.

(S)-3-{6-(Tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-5-ylamine

To a stirred suspension of(S)-{6-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethylamino}-4-(5-methyl-2-furyl)-5-nitropyrimidine-2-amine(4) (24 g, 0.056 mol.) in ethanol (900 mL, 37 volumes), platinum (IV)oxide (crystal, 1.27 g, 0.0056 mol., 10% eq) was added. The flask wasthoroughly evacuated and placed under an atmosphere of hydrogen. After18 hr at 22° C. the former suspension of the starting material was now adark solution of the triamine (confirmed by TLC and a crude ¹H NMR). Thesolution was filtered through a pad of Celite and the filtrate acidifiedwith c. HCl (30 mL). The acidic solution was cooled to 0° C. and treateddropwise with an aqueous solution of sodium nitrite (15.46 g, 0.224 mol,4 eq, 60 mL H₂O). The solution was stirred at 0° C. for 2 hr. Thereaction mixture was basified using saturated aqueous sodium bicarbonate(pH ca. 8). The ethanol solvent was removed in vacuo causing theprecipitation of the product from the remaining aqueous fraction. Thelight brown solid was filtered and dried at 40° C. This method gave20.62 g (90% yield) of the title compound in ca. 95% purity.

Example 1AS-7-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine,alternate synthesis(S)-2-Bromomethyl-6-(tetrahydrofuran-3-yloxymethyl)pyridine

Prepared from 2,6-bis(bromomethyl)pyridine and (S)-tetrahydrofuran-3-olby the alkylation method described for the final step of Example 32 togive the title compound (24%); NMR δ_(H) (400 MHz, CDCl₃) 7.70 (1H, t, J7.5 Hz), 7.39 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 4.67-4.59 (2H,m), 4.52 (2H, s), 4.31-4.26 (1H, m) 3.98-3.81 (4H, m), 2.11-1.99 (2H,m); (M+H)⁺ 272, 274.

(S)-3-{6-(Tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and(S)-2-bromomethyl-6-(tetrahydrofuran-3-yloxymethyl)pyridine by thealkylation method described in Example 36.

Mp: 207.4-207.8° C.; IR v_(max) (DR)/cm⁻¹ 3514, 3294, 3170, 2938, 2868,1631, 1609, 1576, 1540, 1498, 1459 and 1431; NMR δ_(H) (400 MHz, DMSO)7.88 (1H, d, J 3.5 Hz), 7.78 (1H, t, J 8.0 Hz), 7.35 (1H, d, J 8.0 Hz),7.27 (2H, br s), 7.05 (1H, d, J 8.0 Hz), 6.52-6.50 (1H, m), 5.74 (2H,s), 4.51-4.44 (2H, m), 4.23-4.20 (1H, m), 3.76-3.61 (4H, m), 2.46 (3H,s), 1.94-1.89 (2H, m); (M+H)⁺ 408; Anal. Calcd for C₁₆H₁₅N₇O+2 HCl+1.5H₂O: C, 45.62; H, 4.79; N, 23.27. Found: C, 45.63; H, 4.71; N, 23.14.

(R)-3-{6-(Tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and(R)-2-bromomethyl-6-(tetrahydrofuran-3-yloxymethyl)pyridine by thealkylation method described for in Example 36.

mp: 169.7-170.6° C.; IR v_(max) (DR)/cm⁻¹ 3514, 3294, 3171, 2940, 2867,1632, 1574, 1540, 1496, 1457 and 1431; NMR δ_(H) (400 MHz, DMSO) 7.88(1H, d, J 3.5 Hz), 7.78 (1H, t, J 8.0 Hz), 7.35 (1H, d, J 8.0 Hz), 7.27(2H, br s), 7.05 (1H, d, J 8.0 Hz), 6.52-6.50 (1H, m), 5.74 (2H, s),4.51-4.44 (2H, m), 4.23-4.20 (1H, m), 3.76-3.61 (4H, m), 2.46 (3H, s),1.94-1.89 (2H, m); (M+H)⁺ 408.

Example 1BS-7-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine,alternate synthesis 2-Chloromethylpyridine

2-Chloromethylpyridine HCl (120 g, 0.732 mol, 1 eq) was dissolved in 500mL demineralised water. Solid NaHCO₃ (67.60 g, 0.805 mol, 1.1 eq) wasadded in small portions and the mixture was stirred until gas evolutionstopped. The free base was extracted into 2×800 mL ethyl acetate; thecombined extracts were washed with 300 mL saturated brine and evaporatedto give the title compound (90.43 g, 97%) as a red oil.

(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine

A 3-neck flask under a nitrogen-line was charged with anhydrous THF (600mL) through a canule. NaH (60% dispersion in mineral oil, 21.16 g, 0.529mol, 1.5 eq) was suspended in the solvent under vigorous stirring.(S)-(+)-3-hydroxytetrahydrofuran (34.14 g; 0.388 moL, 1.1 eq) was addedand stirred at room temperature for 30 minutes. 2-Chloromethylpyridine(1a; 45.00 g, 0.353 mol, 1 eq) was added neat and the mixture wasstirred at reflux for 16 hours. The reaction mixture was cooled to roomtemperature and quenched with 520 mL saturated aqueous ammonium chloridesolution. THF was removed under reduced pressure and the aqueous residuewas extracted with 2×800 mL ethyl acetate. The combined organic extractswere washed with 250 mL saturated brine, dried over Na₂SO₄ andevaporated to dryness. The brown oily residue was taken up in 520 mLacetonitrile and remaining mineral oil was extracted with 330 mL hexane.Acetonitrile was evaporated in vacuo to leave a brown residue, yield87%; LC-MS Retention time 1.22 min; (M+H)⁺ 180.

(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine-1-oxide

(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine (110.33 g, 0.616 mol, 1eq) was dissolved in 900 mL DCM and cooled in an ice bath.3-Chloroperoxybenzoic acid (151.77 g, 0.677 mol, 1.1 eq) was added andthe solution was warmed to room temperature and stirred overnight. K₂CO₃(85.09 g, 0.616 mol, 1 eq) was added as a solid and stirred for 2 hours.The white precipitate was filtered off and the filter cake washed withdichloromethane. Another portion or K₂CO₃ (85 g, 0.616 mol, 1 eq) wasadded to the filtrate and stirred for 3 days. The white solid wasfiltered off and the filtrate evaporated to give the title compound(119.62 g, 99%) as a yellow oil; LC-MS Retention time 1.27 min; (M+H)⁺196.

(S)-6-(Tetrahydrofuran-3-yloxymethyl)pyridine-2-carbonitrile

(S)-2-(Tetrahydrofuran-3-yloxymethyl)pyridine-1-oxide (24.08 g, 0.123mol, 1 eq) was dissolved in anhydrous DCM (400 mL). N,N-Dimethylcarbamylchloride (19.89 g, 0.185 mol, 1.5 eq) was added followed bytrimethylsilyl cyanide (18.35 g, 0.185 mol, 1.5 eq). The solution wasstirred at 40° C. for 24 hours (solution had turned red). The reactionwas cooled to room temperature, then 2 M aqueous Na₂CO₃ solution wasadded (80 mL) and stirred overnight. The emulsion was filtered off,leaving the white precipitate behind. The layers were separated and theorganic layer was evaporated to leave a brown oil. This was dissolved inethyl acetate (160 mL), 2-M aqueous Na₂CO₃ solution (160 mL) was addedand stirred for 2 hours. The layers were separated and the organic layerwas washed with saturated brine (30 mL), dried over Na₂SO₄ andevaporated to a brown oil; LC-MS Retention time 1.82 min; (M+H)⁺ 205.

(S)-6-(Tetrahydrofuran-3-yloxymethyl)-2-pyridinemethanamine

(S)-6-(Tetrahydrofuran-3-yloxymethyl)pyridine-2-carbonitrile (0.206 mol,1 eq) was added to borane (1-M in THF, 290 mL, 0.290 mol, 3 eq) at 0° C.under nitrogen. The reaction was then heated to reflux for 5 hours,cooled to room temperature and quenched with 100 mL methanol(exothermic) and evaporated. 2 M aqueous HCl (310 mL) was added (pH 1)to the combined residues. After the quench, the mixture was brought topH 7 with 5 M NaOH (35 mL). The aqueous mixture was extracted with 2×500mL dichloromethane. These organic extracts were discarded. The aqueousphase was brought to pH 14 with 5-N NaOH (100 mL) and extracted with2×1000 mL DCM. The combined organic extracts (from alkaline solution)were washed with 100 mL saturated brine, dried over Na₂SO₄ andevaporated to give the title compound (50.70 g, 39% over 2 steps) as anamber oil; LC-MS Retention time 0.62 min; (M+H)⁺ 205.

Example 27-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine and2-(6-bromomethylpyridine-2-yl)propan-2-ol by the alkylation methoddescribed in Example 36.

IR v_(max) (DR)/cm⁻¹ 3487, 3335, 3120, 2974, 2926, 1517, 1540, 1491 and1418; NMR δ_(H) (400 MHz, DMSO) 7.88 (1H, d, 73.5 Hz), 7.74 (1H, t, J8.0 Hz), 7.54 (1H, d, J 8.0 Hz), 7.30 (2H, br s), 6.95 (1H, d, J 8.0Hz), 6.52-6.51 (1H, m), 5.76 (2H, s), 5.15 (1H, s), 2.46 (3H, s), 1.27(6H, s); (M+H)⁺ 366.

Example 37-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-(1-Hydroxy-1-cyclopentyl)pyridine

Prepared from 2-bromopyridine and cyclopentanone by the method describedin Example 10.

2-(1-Hydroxy-1-cyclopentyl)pyridine-N-oxide

Prepared from 2-(1-hydroxy-1-cyclopentyl)pyridine by the methoddescribed above for Example 10; NMR δ_(H) (400 MHz, CDCl₃) 1.68-1.78(2H, m), 1.96-2.06 (4H, m), 2.26-2.35 (2H, m), 7.14 (1H, s), 7.24 (1H,dd, J 6.5 Hz, 2.0 Hz), 7.32-7.41 (2H, m), 8.26 (1H, dd, J 6.0 Hz, 1.0Hz); (M+H)⁺ 180.

6-(1-Hydroxy-1-cyclopentyl)pyridine-2-carbonitrile

Prepared from 2-(1-hydroxy-1-cyclopentyl)pyridine-N-oxide by the methoddescribed above for Example 10; NMR δ_(H) (400 MHz, CDCl₃) 1.74-1.94(6H, m), 2.15-2.22 (2H, m), 7.49 (1H, dd, J 7.5 Hz, 1.5 Hz), 7.72-7.80(2H, m)

6-(1-Hydroxy-1-cyclopentyl)pyridine-2-methanamine

Prepared from 6-(1-hydroxy-1-cyclopentyl)pyridine-2-carbonitrile by themethod described in Example 10; NMR δ_(H) (400 MHz, CDCl₃) 1.48 (2H, s),1.66-1.75 (2H, m), 1.78-1.92 (6H, m), 3.83 (2H, s), 5.12 (1H, s), 7.01(1H, d, J 7.5 Hz), 7.08 (1H, d, J 8.0 Hz), 7.51 (1H, t, J 8.0 Hz);(M+H)⁺ 194.

N-(2-amino-6-chloro-4-[6-(1-hydroxy-1-cyclopentyl)pyridine-2-methylamino]pyrimidin-5-yl)formamide

Prepared from N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide and6-(1-hydroxy-1-cyclopentyl)pyridine-2-methanamine by the methoddescribed in Example 10 to give the title compound (0.256 g, 47%) as acream powder, NMR δ_(H) (400 MHz, DMSO) 1.68-1.80 (4H, m), 1.81-1.92(2H, m), 2.04-2.12 (2H, m), 4.56 (2H, d, J 5.5 Hz), 5.01 (1H, s), 6.45(2H, s), 7.11 (1H, d, J 8.0 Hz), 7.34 (1H, t, J 6.0 Hz), 7.52 (1H, d, J7.5 Hz), 7.69 (1H, t, J 7.5 Hz), 8.19 (1H, s), 9.21 (1H, s); (M+H)⁺ 363.

7-Chloro-3-(6-[1-hydroxy-1-cyclopentyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine

Prepared fromN-(2-amino-6-chloro-4-[6-(1-hydroxy-1-cyclopentyl)pyridine-2-methylamino]pyrimidin-5-yl)formamideby the method described in Example 10; NMR δ_(H) (400 MHz, DMSO)1.44-1.51 (2H, m), 1.55-1.62 (2H, m), 1.67-1.76 (4H, m), 4.96 (1H, s),5.78 (2H, s), 7.07 (1H, d, J 7.0 Hz), 7.54 (1H, d, J 8.5 Hz), 7.61 (2H,s), 7.73 (1H, t, J7.5 Hz); (M+H)⁺ 335.

3-(6-[1-hydroxy-1-cyclopentyl]pyridine-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine

Prepared from7-chloro-3-(6-[1-hydroxy-1-cyclopentyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineby the method described in Example 10.

IR v_(max) (DR)/cm⁻¹ 3325, 3203, 2959, 2871, 1537, 1504, 1433, 1325,1206, 1107, 1026 and 794; NMR δ_(H) (400 MHz, DMSO) 1.47-1.55 (2H, m),1.57-1.63 (2H, m), 1,67-1.76 (2H, m), 1.80-1.87 (2H, m), 2.46 (3H, s),4.97 (1H, s), 5.76 (2H, s), 6.50 (1H, dd, J 3.5 Hz, 1.0 Hz), 6.98 (1H,d, J 7.5 Hz), 7.23 (2H, s), 7.55 (1H, d, J 7.5 Hz), 7.72 (1H, t, J 7.5Hz), 7.87 (1H, d, J 3.0 Hz); (M+H)+ 392.

Example 47-(5-methylfuran-2-yl)-3-(6-[1-hydroxy-1-cyclohexyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine1-(6-[tert-Butyldimethylsilyloxymethyl]pyridine-2-yl)-1-cyclohexanol

Prepared from 6-bromo-O-(tert-butyldimethylsilyl)-2-pyridinemethanol andcyclohexanone by the method described in Example 10 to give the titlecompound (0.49 g, 15%) as a yellow oil; NMR δ_(H) (400 MHz, CDCl₃) 0.13(6H, s), 0.96 (9H, s), 1.61-1.91 (10H, m), 4.82 (2H, s), 5.17 (1H, s),7.21 (1H, dd, J 8.0 Hz, 1.0 Hz), 7.38 (1H, dd, J 7.5 Hz), 1.0 Hz), 7.71(1H, t, J 7.5 Hz). TLC (Hex:EtOAc (9:1)) Rf=0.30**

6-(1-Hydroxy-1-cyclohexyl)-2-pyridinemethanol

Prepared from1-(6-[tert-butyldimethylsilyloxymethyl]pyridine-2-yl)-1-cyclohexanol bythe method described for the final step in Example 27 to give the titlecompound (0.35 g, quantitative) as a yellow oil; NMR δ_(H) (400 MHz,CDCl₃) 1.67-1.89 (10H, m), 3.73-3.77 (1H, m), 4.78 (2H, s), 7.17 (1H, d,J 7.5 Hz), 7.34 (1H, d, J 8.0 Hz), 7.71 (1H, t J 7.5 Hz); (M+H)⁺ 208.

1-(6-Bromomethylpyridine-2-yl)-1-cyclohexanol

Prepared from 6-(1-hydroxy-1-cyclohexyl)-2-pyridinemethanol by thebromination method described in Example 31 to give the title compound(0.30 g, 44%) as a yellow oil; NMR δ_(H) (400 MHz, CDCl₃) 1.62-1.89(10H, m), 4.55 (2H, s), 4.89 (1H, s), 7.30 (1H, dd, J 8.0 Hz, 1.0 Hz),7.34 (1H, dd, J 7.5 Hz, 1.0 Hz), 7.71 (1H, t, J 7.5 Hz); (M+H)⁺ 270.

3-(6-[1-hydroxy-1-cyclohexyl]pyridine-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine

Prepared from7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and1-(6-bromomethylpyridine-2-yl)-1-cyclohexanol by the alkylation methoddescribed in Example 36.

IR v_(max) (DR)/cm⁻¹ 3321, 3205, 2931, 2857, 1604, 1573, 1537, 1503,1433, 1326, 1206 and 794; NMR δ_(H) (400MHz, DMSO) 0.81-0.87 (1H, m),1.02-1.15 (1H, m), 1.33-1.43 (4H, m), 1.50-1.73 (4H, m), 2.46 (3H, s),4.87 (1H, s), 5.76 (2H, s), 6.51 (1H, dd, J 3.5 Hz, 1.0 Hz), 6.95 (1H,d, J 7.5 Hz), 7.29 (2H, s), 7.53 (1H, d, J 8.0 Hz), 7.73 (1H, t, J 7.5Hz), 7.88 (1H, d, J 3.5 Hz).

Example 57-(5-methylfuran-2-yl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared as in Example 10 from7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineand 5-methyl-2-furanboronic acid as described above to give the titlecompound.

IR v_(max) (DR)/cm⁻¹ 3305, 3206, 2956, 1731, 1680, 1622, 1494, 1372,1226, 1142, 1029 and 792; NMR δ_(H) (400 MHz, DMSO) 1.39 (2H, d, J 12.5Hz), 2.09 (2H, dt, J 12.5 Hz), 2.45 (3H, s), 3.63-3.73 (4H, m), 5.28(1H, s), 5.97 (2H, s), 6.49 (1H, d, J 3.5 Hz), 7.03 (2H, s), 7.11 (1H,d, J 7.5 Hz), 7.63 (1H, d, J 7.5 Hz), 7.70 (1H, d, J 3.5 Hz), 7.82 (1H,t, J 7.5 Hz); (M+H)⁺ 408.

Example 67-(5-methylfuran-2-yl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine4-(6-[1-(hydroxy-1-cyclobutyl]pyridine-2-methylamino)-6-(5-methyl-2-furyl)-5-nitropyrimidine-2-amine

Prepared from6-(5-methyl-2-furyl)-5-nitro-4-(p-toluenesulphonyloxy)pyrimidine-2-amineand 6-(1-hydroxy-1-cyclobutyl)pyridine-2-methanamine by the methoddescribed for Example 1 to give the title compound (0.14 g, 38%) as ayellow solid; NMR δ^(H) (400 MHz, DMSO) 8.90 (1H, br t), 7.75 (1H, t, J7.7 Hz), 7.47 (1H, d, J 7.7 Hz), 7.34 (2H, br s), 7.21 (1H, d, J 7.7Hz), 6.90 (1H, d, J 2.9 Hz), 6.27 (1H, d, J 2.9 Hz), 5.71 (1H, br s),4.78 (2H, d, J 3.9 Hz), 2.59 (2H, m), 2.30 (3H, s), 2.20 (2H, m), 1.89(2H, m); (M+H)⁺397.

3-{6-[1-Hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from4-(6-[1-hydroxy-1-cyclobutyl]pyridine-2-methylamino)-6-(5-methyl-2-furyl)-5-nitropyrimidine-2-amineby the method described in Example 1 to give the title compound (0.05 g,38%) as a beige solid.

NMR δ_(H) (400 MHz, DMSO) 1.36-1.44 (1H, m), 1.61-1.69 (1H, m),2.03-2.10 (2H, m), 2.19-2.25 (2H, m), 2.46 (3H, s), 5.62 (1H, s), 5.81(2H, s), 6.51 (1H, d, J 2.5 Hz), 7.08 (1H, d, J 7.5 Hz), 7.22 (2H, b),7.44 (1H, d, J 8.0 Hz), 7.73 (1H, t, J 8.0 Hz), 7.87 (1H, d, J 3.5 Hz);(M+H)⁺ 378.

Example 7S-7-phenyl-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineN-[2-Amino-4-chloro-6-({6-[(S)-(tetrahydro-furan-3-yl)oxymethyl]pyridin-2-ylmethyl}amino)pyrimidin-5-yl]formamide

A mixture of N-(2-amino-4,6-dichloropyrmidin-5-yl)formamide (17.24 g,82.46 mmol),6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethylamine (18.89 g,90.70 mmol) and triethylamine (12.64 mL, 90.70 mmol) in propan-2-ol (165mL) was heated at reflux for 2 h, cooled and the resulting precipitatewas stirred, washed with cold propan-2-ol and dried to give the titlecompound (22.66 g, 73%) as a pink solid; LC-MS retention time 1.46 min,(M+H)⁺ 379.

6-chloro-N⁴-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}primidine-2,4,5-triamine

A mixture ofN-[2-amino-4-chloro-6-({6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-amino)pyrimidin-5-yl]formamide(10.00 g, 26.40 mmol) and hydrochloric acid (6 M, 22 mL) in EtOH (100mL) was heated at reflux for 15 h, cooled, basified with aqueous sodiumhydroxide (5-M, 50 mL) and concentrated in vacuo to remove the EtOH. Theresulting mixture was extracted with dichloromethane (×2) and thecombined organic extracts were washed with saturated brine, dried(Na₂SO4) and concentrated in vacuo to give the title compound (8.09 g,87%) as a pink solid; LC-MS retention time 1.52 min; (M+H)⁺ 351.

7-Chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of6-chloro-N⁴-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}pyrimidine-2,4,5-triamine(8.09 g, 23.06 mmol) in EtOH (85 mL) and glacial acetic acid (21 mL) at0° C., was treated with a solution of sodium nitrite (2.07 g, 29.979mmol) in water (5.3 mL), stirred at 0° C. for 1 h and the resultingprecipitate was filtered, washed with EtOH (85 mL) and dried to give thetitle compound (5.82 g, 70%) as an off-white solid; LC-MS retention time1.94 min, (M+H)⁺ 362.

7-Phenyl-3-[6-(tetrahydro-furan-3-yloxymethyl)pyridin-2-ylmethyl]-3H-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

This was prepared from7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand phenylboronic acid by the method of Example 13 to give 0.060 g(68%).

NMR δ_(H) (400 MHz, d₆-DMSO) 8.77-8.74 (2H, m), 7.79 (1H, t, J 8 Hz),7.67-7.63 (3H, m), 7.35 (1H, d, J 8 Hz), 7.33 (2H, br s), 7.08 (1H, d, J8 Hz), 5.79 (2H, s), 4.49-4.47 (2H, m), 4.23-4.20 (1H, m), 3.75-3.61(4H, m) and 1.93-1.89 (2H, m); LC-MS Retention time 2.28 min; (M+H)⁺404.

Example 8 7-phenyl-3(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared as described in Example 20 from7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine(0.25 g, 0.78 mml) and 3-phenylboronic acid (0.11 g, 0.93 mmol) to givethe title compound (48 mg, 17%) as a white powder.

NMR δ_(H) (400 MHz, CDCl₃) 8.76 (2H, m), 7.73 (1H, t, J 7.7 Hz), 7.62(3H, m), 7.55 (1H, d, J 4.3 Hz), 7.30 (2H, br s), 6.98 (1H, d, J 7.7Hz), 5.80 (2H, s), 5.12 (1H, s), 1.26 (6H, s); LC-MS Retention time 2.26min; (M+H)⁺ 362.

Example 9 7-phenyl-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from7-chloro-3-(6-[1-hydroxy-1-cyclopentyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineby the method described in Example 10.

IR v_(max) (DR)/cm⁻¹ 3316, 3200, 2963, 1740, 1602, 1505, 1429, 1236,1010 and 772. NMR δ_(H) (400 MHz, DMSO) 1.41-1.51 (2H, m), 1.55-1.62(2H, m), 1.64-1.73 (2H, m), 1.76-1.83 (2H, m), 4.96 (1H, s), 5.81 (2H,s), 7.02 (1H, d, J 7.5 Hz), 7.26 (2H, s), 7.55 (1H, d, J 8.0 Hz),7.62-7.67 (3H, m), 7.73 (1H, t, J 7.5 Hz).

Example 107-phenyl-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-(4-Hydroxytetrahydropyran-4-yl)pyridine

To a stirred, cooled solution of 2-bromopyridine (5 g, 31.65 mmol) inTHF (75 mL) at −78° C. was added n-butyl lithium (2.5 M in hexanes,12.66 mL, 31.65 mmol) dropwise and the solution stirred at −78° C. for10 minutes. After this time, tetrahydro-4H-pyran-4-one (3.49 g, 34.81mmol) was added, the reaction warmed to ambient temperature and stirredovernight. The reaction was then quenched with saturated aqueousammonium chloride solution and the THF removed in vacuo. The resultantaqueous phase was twice extracted with ethyl acetate and the combinedorganic phases dried (magnesium sulfate) and filtered. Afterconcentration in vacuo, purification by column chromatography (SiO₂,eluting with 2:1 hexanes:ethyl acetate) gave a residue which wastriturated from hexane to yield the title compound (3.47 g, 61%) as awhite solid; NMR δ_(H) (400 MHz, CDCl₃) 8.49 (1H, m), 7.81 (1H, td, J7.8 Hz, 1.8 Hz), 7.68 (1H, m), 7.25 (1H, ddd, J 7.5 Hz, 4.9 Hz, 1.1 Hz),3.85 (4H, m), 3.30 (1H, m), 2.30 (2H, td, J 13.3 Hz, 5.3 Hz), 1.54 (1H,dd, J 13.8 Hz, 1.9 Hz); LC-MS Retention time 0.51 min, (M+H)⁺ 180.

2-(4-Hydroxytetrahydropyran-4-yl)pyridine-N-oxide

To a stirred solution of 2-(4-hydroxytetrahydropyran-4-yl)pyridine (2.08g, 11.6 mmol) in dichloromethane (100 mL) was added, with stirring,m-CPBA (77%, 2.86 g, 12.76 mmol) and the mixture stirred at ambienttemperature overnight. After this time, potassium carbonate (1.62 g,11.60 mmol) was added, the reaction stirred for two hours and themixture filtered. A further aliquot of potassium carbonate (1.62 g,11.60 mmol) was added to the filtrate and the mixture again stirred fortwo hours. After filtration and concentration in vacuo, the N-oxide wasobtained as a pale brown solid (2.28 g, quant.) and used without furtherpurification; NMR δ_(H) (400 MHz, DMSO) 8.33 (1H, dd, J 6.3 Hz, 1.1 Hz),7.65 (1H, dd, J 8.0 Hz, 2.0 Hz), 7.52 (1H, td, J 7.9 Hz, 1.3 Hz), 7.44(1H, td, J 7.6 Hz, 2.0 Hz), 7.32 (1H, br s), 3.78 (4H, m), 2.23 (2H, td,J 12.5 Hz, 5.1Hz), 1.80 (1H, d, J 11.4 Hz); LC-MS Retention time 0.99min, (M+H)⁺ 196.

6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-carbonitrile

To a stirred solution of2-(4-hydroxytetrahydropyran-4-yl)pyridine-N-oxide (3.69 g, 18.91 mmol)in anhydrous dichloromethane was added dimethylcarbamoyl chloride (3.05g, 28.4 mmol) and trimethylsilylcyanide (2.82 g, 28.4 mmol). The mixturewas stirred for sixty hours at 40° C., after which time further aliquotsof dimethyl carbamoyl chloride (3.05 g, 28.4 mmol) andtrimethylsilylcyanide (2.82 g, 28.4 mmol) were added. After stirring at40° C. for a further 24 hours, sodium carbonate solution (50 mL, 2 Maqueous solution) was added and the mixture stirred overnight. Theresultant mixture was filtered and the layers partitioned. Sodiumcarbonate solution (50 mL, 2 M aqueous solution) was again added to theorganic phase and stirred overnight. After separation of the phases, theorganic layer was blown down at ambient temperature to give the titlecompound as a brown oil which was used in the next step without furtherpurification; LC-MS Retention time 1.62 min, (M+H)⁺ 205.

6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-methanamine

6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-carbonitrile (ca. 18.9 mmol)was dissolved in anhydrous THF (80 mL) and a 1 M solution of BH₃ in THF(95 mL, 95 mmol) added. The solution was stirred at ambient temperaturefor 2.5 hours, then quenched with methanol. The solution was adjusted topH 1 by addition of 2 N hydrochloric acid solution and then neutralisedto pH 5 with a 5 N solution of sodium hydroxide. Extraction withdichloromethane was followed by addition of further 2 N sodium hydroxideto the aqueous phase until the pH reached 14. This phase was twiceextracted with dichloromethane and these combined extracts wereevaporated to give a yellow gum. The aqueous extracts were acidifiedwith 2 N hydrochloric acid and concentrated to dryness to yield a whiteresidue. Three triturations of this residue with methanol andconcentration of the methanolic liquors yielded a second crop of yellowgum. Drying in vacuo gave the title compound (2.51 g, 64%) as a foamyyellow solid; NMR δ_(H) (400 MHz, DMSO) 8.53 (1H, br s), 7.85 (1H, t, J7.8 Hz), 7.62 (1H, d, J 7.8 Hz), 7.34 (1H, d, J 7.5 Hz), 5.75 (1H, s),3.72 (4H, m), 3.16 (2H, s), 2.29 (2H, m), 1.42 (1H, d, J 12.3 Hz); LC-MSRetention time 0.43 min, (M+H)⁺ 209.

7-Chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine

Prepared from 2-amino-4,6-dichloro-5-formylaminopyrimidine (1.77 g, 8.55mmol) and 6-(4- hydroxytetrahydropyran-4-yl)pyridine-2-methanamine (1.96g, 9.71 mmol) by the method described in reference example 1 to give thetitle compound (0.42 g, 14%) as a brown powder; NMR δ_(H) (400 MHz,DMSO) 7.77 (1H, t, J 7.7 Hz), 7.65 (2H, br s), 7.56 (1H, d, J 7.5 Hz),7.07 (1H, d, J 7.7 Hz), 5.77 (2H, s), 5.19 (1H, s), 3.63 (4H, m), 1.90(2H, m), 1.31 (2H, d, J 11.9 Hz); LC-MS Retention time 1.83 min, (M+H)⁺362.

3-(6-[4-Hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine

A solution of the7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine(0.10 g, 0.27 mmol) and phenylboronic acid (0.05 g, 0.41 mmol) andpotassium phosphate (0.12 g, 0.55 mmol) in 1,4-dioxane (5 mL) wasdegassed by sparging with nitrogen. Tetrakis triphenylphosphinepalladium (16 mg) was then added, the solution degassed again and theresultant mixture heated at 100° C. for seven hours. The mixture wasthen concentrated onto Isolute-HM in vacuo, purified by columnchromatography (silica, eluting with 3:1 ethyl acetate:hexane and neatethyl acetate) and triturated with diethyl ether to give the titlecompound (41 mg, 37%) as a pale beige solid.

NMR δ_(H) (400 MHz, DMSO) 8.76 (2H, m), 7.77 (1H, t, J 7.8 Hz), 7.64(3H, m), 7.57 (1H, d, J 7.5 Hz), 7.31 (2H, br s), 7.02 (1H, d, J 7.5Hz), 5.81 (2H, s), 5.20 (1H, s), 3.60 (4H, m), 1.97 (2H, m), 1.33 (2H,d, J 12.0 Hz); LC-MS Retention time 2.17 min; (M+H)⁺ 404.

Example 11 7-phenyl-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-(1-Hydroxy-1-cyclobutyl)pyridine

Prepared from 2-bromopyridine and cyclobutanone by the method describedin Example 10 to give the title compound (7.62 g, quantitative) as anorange oil; NMR δ_(H) (400 MHz, DMSO) 8.54 (1H, m), 7.75 (1H, td, J 7.6,1.7 Hz), 7.59 (1H, m), 7.22 (1H, m), 5.70 (1H, s), 2.58 (2H, m), 2.23(2H, m), 1.91 (2H, m); (M+H)⁺ 151.

2-(1-Hydroxy-1-cyclobutyl)pyridine-N-oxide

Prepared from 2-(1-hydroxy-1-cyclobutyl)pyridine by the method describedin Example 10 to give the title compound as a yellow oil; NMR δ_(H) (400MHz, DMSO) 8.36 (1H, dd, J 6.3, 1.1 Hz), 8.31 (1H, s), 7.67 (1H, dd, J8.1, 2.1 Hz), 7.50 (1H, td, J 8.7, 1.1 Hz), 7.44 (1H, m), 6.84 (1H, s),2.51 (2H, m), 2.27 (2H, m), 1.94 (2H, m); (M+H)⁺ 167.

6-(1-Hydroxy-1-cyclobutyl)pyridine-2-carbonitrile

Prepared from 2-(1-hydroxy-1-cyclobutyl)pyridine-N-oxide by the methoddescribed in Example 10 to give the title compound (1.66 g, 21%); NMRδ_(H) (400 MHz, DMSO) 8.02 (1H, app t, J 8.0 Hz), 7.89 (1H, d, J 2.7Hz), 7.87 (1H, dd, J 3.0, 0.9 Hz), 5.96 (1H, s), 2.54 (2H, m), 2.25 (2H,m), 1.94 (1H, m), 1.79 (1H, m); (M+H)⁺ 177.

6-(1-Hydroxy-1-cyclobutyl)pyridine-2-methanamine

Prepared from 6-(1-hydroxy-1-cyclobutyl)pyridine-2-carbonitrile by themethod described in Example 10 to give the title compound (0.87 g, 53%)as a yellow oil; NMR δ_(H) (400 MHz, DMSO) 7.68 (1H, t, J 7.8 Hz), 7.40(1H, d, J 7.6 Hz), 7.25 (1H, d, J 7.6 Hz), 5.73 (1H, s), 3.82 (2H, s),2.55 (2H, m), 2.22 (2H, m), 1.83 (2H, m); (M+H)⁺ 181.

N-(2-amino-6-chloro-4-[6-(1-hydroxy-1-cyclobutyl)pyridine-2-methylamino]pyrimidin-5-yl)formamide

Prepared from N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide and6-(1-hydroxy-1-cyclobutyl)pyridine-2-methanamine by the method describedin Example 7 to give the title compound (0.92 g, 85%) as an orangesolid; NMR δ_(H) (400 MHz, DMSO) 9.77 (1H, s), 9.22 (1H, s), 7.70 (1H,t, J 7.7 Hz), 7.65 (2H, br s), 7.57 (1H, d, J 9.7 Hz), 7.37 (1H, t, J5.7 Hz), 7.14 (1H, d, J 7.7 Hz), 5.66 (1H, s), 5.40 (2H, d, J 5.7 Hz),2.52 (2H, m), 2.19 (2H, m), 1.90 (1H, m), 1.81 (1H, m); (M+H)⁺ 350.

7-Chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared fromN-(2-amino-6-chloro-4-[6-(1-hydroxy-1-cyclobutyl)pyridine-2-methylamino]pyrimidin-5-yl)formamideby the method described in Example 7 to give the title compound (0.12 g,66%) as an orange solid; NMR δ_(H) (400 MHz, DMSO) 7.74 (1H, t, J 7.8Hz), 7.60 (2H, br s), 7.43 (1H, d, J 7.8 Hz), 7.15 (1H, d, J 7.6 Hz),5.83 (2H, s), 5.62 (1H, s), 2.12 (2H, m), 2.04 (2H, m), 1.64 (1H, m),1.29 (1H, m); (M+H)⁺ 332.

3-{6-[1-Hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand phenylboronic acid by the method described in Example 7 to give thetitle compound (0.03 g).

NMR δ_(H) (400 MHz, DMSO) 1.32-1.39 (1H, m), 1.59-1.66 (1H, m),2.01-2.09 (2H, m), 2.18-2.24 (2H, m), 5.62 (1H, s), 5.87 (2H, s), 7.10(1H, d, J 8.0 Hz), 7.25 (2H, b), 7.43 (1H, d, J 8.0 Hz), 7.62-7.66 (3H,m), 7.74 (1H, t, J 7.5 Hz), 8.74-8.77 (2H, m); (M+H)⁺ 374.

Example 127-phenyl-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

The title compound was prepared from7-chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineand the appropriate arylboronic acid by the method described inreference example 1.

NMR δ_(H) (400 MHz, DMSO) 8.75 (2H, m), 8.35 (2H, br s), 7.78 (1H, t, J6.9 Hz), 7.64 (2H, m), 7.34 (2H, br s), 7.04 (1H, d, J 7.6 Hz), 5.78(2H, s), 4.43 (2H, s), 3.37 (3H, s); LC-MS Retention time 2.25 min;(M+H)⁺ 348.

Example 13S-7-(3-methoxyphenyl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

A solution of7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine(0.100 g, 0.276 mmol) and 3-methoxyphenylboronic acid (0.084 g, 0.55mmol) in 1,4-dioxane (4 mL) and saturated brine (1 mL) was degassed withnitrogen, treated with tetrakis(triphenylphosphine)palladium(0) (0.016g, 0.014 mmol), heated at 90° C. for 6.5 h then partitioned betweenwater and EtOAc. The organic phase was separated and the aqueous phasewas re-extracted with EtOAc, the combined organic extract was dried(Na₂SO₄), concentrated in vacuo and the resulting brown solid (0.150 g)purified by semi-preparative LC-MS to give the title compound (0.052 g,43%) as an off-white solid.

NMR δ_(H) (400 MHz, d₆-DMSO) 8.39 (1H, dt, J 7.5, 1 Hz), 8.30 (1H, dd, J2.5, 0.5 Hz), 7.79 (1H, t, J 7.5 Hz), 7.65-7.53 (3H, m), 7.37 (2H, brs), 7.24 (1H, ddd, J 8.5, 2.5, 1 Hz), 7.09 (1H, d, J 7.5 Hz), 5.78 (2H,S), 4.47 (2H, s), 4.23-4.19 (1H, m), 3.88 (3H, s), 3.76-3.60 (4H, m) and1.93-1.88 (2H, m.); LC-MS Retention time 2.32 mm; (M+H)⁺ 434.

Example 147-(3-methoxyphenyl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine

To a solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine(5.1 g, 30.5 mmol) in dicholoromethane (300 mL) was added carbontetrabromide (8.81 g, 33.6 mmol) and triphenylphosphine (11.14 g, 33.6mmol). The reaction was stirred at ambient temperature overnight thenpoured into a saturated solution of sodium bicarbonate. The organiclayer was separated, concentrated to dryness and purified by columnchromatography, eluting with a gradient of hexane to 3:1 hexane:ethylacetate. The title compound (5.21 g, 74%) was obtained as a colourlessoil; LC-MS Retention time 2.08 min, (M+H)⁺ 230, 232

2-Azidomethyl-6-(1-hydroxy-1-methylethyl)pyridine

2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine (7.61.g, 33 mmol) wasdissolved in dimethylformamide (100 mL) and sodium azide (2.6 g, 39.7mmol) added. After stirring the resultant mixture overnight at ambienttemperature, the reaction was poured into dicholoromethane and washedwell with water. The organic layer was dried (magnesium sulphate),filtered and concentrated to dryness. The resulting yellow oil (5.88 g,93%) was used without further purification; NMR δ_(H) (400 MHz, CDCl₃)7.70 (1H, t, J 7.8 Hz), 7.30 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 7.8 Hz),4.82 (1H, br s), 4.42 (2H, s), 1.51 (6H, s); LC-MS Retention time 2.06min, (M+H)⁺ 193.

6-(1-Hydroxy-1-methylethyl)pyridine-2-methanamine

2-Azidomethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.88 g, 30.6 mmol)was dissolved in methanol (100 mL) and palladium (5% w/w on carbon)added. The suspension was gently agitated under a hydrogen atmosphereovernight, filtered though celite and concentrated to dryness to give4.61 g (90%) of the amine as a colorless oil; NMR δ_(H) (400 MHz, CDCl₃)7.63 (1H, t, J 7.8 Hz), 7.19 (1H, d, J 7.8 Hz), 7.12 (1H, d, J 7.6 Hz),3.93 (2H, s), 1.49 (6H, s); LC-MS Retention time 0.42 min, (M+H)⁺ 167.

7-Chloro-3-(6-[1-hydroxy-1-methylethyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

A solution of the 6-(1-hydroxy-1-methylethyl)pyridine-2-methanamine (2.5g, 15.0 mmol), 2-amino-4,6-dichloro-5-formylaminopyrimidine (3.12 g,15.0 mmol) and triethylamine (4.2 mL, 30 mmol) in isopropyl alcohol (35mL) was heated at 90° C. for four hours, then cooled to 0° C. and pouredinto iced water. This mixture was filtered and the liquors concentratedto dryness. The resultant solids were re-dissolved in ethanol (35 mL)and concentrated hydrochloric acid (12 M, 2.5 mL, 30 mmol) added. Thismixture was then heated at 90° C. for two hours before again cooling to0° C. A solution of sodium nitrite (1.24 g, 18 mmol) in water (2.5 mL)was added dropwise and the mixture stirred at 0° C. for 30 minutes.After pouring into iced, saturated sodium bicarbonate solution andremoval of the residual ethanol in vacuo followed by filtration anddrying in vacuo, the title compound (2.25 g, 47%) was obtained as ared/brown powder; NMR δ_(H) (400 MHz, CDCl₃) 7.66 (1H, t, J 7.7 Hz),7.28 (1H, d, J 7.8 Hz), 7.02 (1H, d, J 7.7 Hz), 5.77 (2H, d), 5.45 (2H,br s), 1.47 (6H, s); LC-MS Retention time 1.89 min, (M+H)⁺ 320.

3-(6-[1-Hydroxy-1-methylethyl]pyridin-2-ylmethyl)-7-(3methoxyphenynl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine

Prepared as described in Example 20 from7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineand 3-methoxyphenylboronic acid (0.08 g, 0.56 mmol) to give the titlecompound (68 mg, 37%) as a yellow solid.

NMR δ_(H) (400 MHz, CDCl₃) 8.49 (1H, d, J 7.7 Hz), 8.38 (1H, br s), 7.64(1H, t, 8.0 Hz), 7.47 (1H, t, J 8.0 Hz), 7.27 (1H, d, J 7.9 Hz), 7.13(1H, dd, J 7.9 Hz, 3.4 Hz), 6.99 (1H, d, J 7.7 Hz) 5.84 (2H, s), 5.45(2H, br s), 3.93 (2H, s), 1.49 (6H, s); LC-MS Retention time 2.27 min;(M+H)⁺ 392.

Example 157-(3-methoxyphenyl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from7-chloro-3-(6-[1-hydroxy-1-cyclopentyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineby the method described above in Example 10.

IR v_(max) (DR)/cm⁻¹ 3375, 3187, 2954, 1602, 1522, 1219, 1017 and 793;NMR δ_(H) (400 MHz, DMSO) 1.42-1.52 (2H, m), 1.57-1.84 (6H, m), 3.88(3H, s), 4.96 (1H, s), 5.81 (2H, s), 7.02 (1H, d, J 7.5 Hz), 7.22-7.28(3H, m), 7.54-7.58 (2H, m), 7.73 (1H, t, J 8.0 Hz), 8.29-8.30 (1H, m),8.38 (1H, dt, J 8.0, 1.5 Hz); (M+H)⁺ 418.

Example 167-(3-methoxyphenyl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineand 3-methoxyphenylboronic acid (0.08 g, 0.55 mmol) as described inExample 10 to give the title compound (45 mg, 38%) as a solid.

NMR δ_(H) (400 MHz, DMSO) 8.40 (1H, dt, J 7.9, 1.1 Hz), 8.30 (1H, m),7.77 (1H, t, J 7.8 Hz), 7.56 (2H, t, J 8.1 Hz), 7.31 (2H, br s), 7.24(1H, m), 7.02 (1H, d, J 7.2 Hz), 5.81 (2H, s), 5.43 (1H, s), 3.69 (3H,s), 3.58 (4H, m), 3.41 (2H, m), 1.33 (2H, d, J 12.2 Hz); LC-MS Retentiontime 2.18 min; (M+H)⁺ 434.

Example 177-(3-methoxyphenyl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand 3-methoxyphenylboronic acid by the method described in Example 7 togive the title compound (0.04 g, 16%).

NMR δ_(H) (400 MHz, DMSO) 1.32-1.38 (1H, m), 1.57-1.66 (1H, m),2.01-2.09 (2H, m), 2.17-2.24 (2H, m), 3.88 (3H, s), 5.63 (1H, s), 5.86(2H, s), 7.10 (1H, d, J 7.5 Hz), 7.22-7.30 (3H, m), 7.43 (1H, d, J 7.5Hz), 7.56 (1H, t, J 8.0 Hz), 7.74 (1H, t, J 7.5 Hz), 8.30 (1H, s), 8.40(1H, d, J 7.5 Hz); (M+H)⁺ 404.

Example 18 7-(3-methoxyphenyl)-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

The title compound was prepared from7-chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineand the appropriate arylboronic acid by the method described inreference example 1.

Example 19S-7-(3-cyanophenyl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

This was prepared from7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand 3-cyanophenylboronic acid by the method of Example 13 to give 0.039g (33%).

NMR δ_(H) (400 MHz, d₆-DMSO) 9.04 (1H, s), 8.14 (1H, d, J 8.0 Hz), 7.89(1H, t, J 8.0 Hz), 7.80 (1H, t, J 7.5 Hz), 7.50 (2H, br s), 7.36 (1H, d,J 7.5 Hz), 7.09 (1H, d, J 7.5 Hz), 5.81 (2H, s), 4.47 (2H, s), 4.25-4.18(1H, m), 3.75-3.60 (4H, m) and 1.93-1.90 (2H, m); LC-MS Retention time2.29 min; (M+H)⁺ 429.

Example 207-(3-cyanophenyl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

A solution of the7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine(0.15 g, 0.47 mmol) and 3-cyanophenylboronic acid (0.08 g, 0.56 mmol) inTHF (5 mL) and saturated sodium bicarbonate solution (0.8 mL) wasdegassed under three alternating cycles of vacuum and nitrogen. Tetrakistriphenylphosphine palladium (50 mg) was then added, the solutiondegassed again and the resultant mixture heated at 70° C. overnight. Themixture was cooled to ambient temperature and loaded directly onto apre-packed 20 g silica column. This was eluted using a gradient ofdichloromethane to dichloromethane:methanol 95:5 to give a yellow waxyoil which was further purified by preparative HPLC to give the titlecompound (15 mg, 8%) as a yellow powder.

NMR δ_(H) (400 MHz, CDCl₃) 9.17 (1H, dt, J 8.1, 1.4 Hz), 9.11 (1H, brs), 7.83 (1H, dt, J 7.8, 1.3 Hz), 7.66 (2H, m), 7.28 (1H, d, J 7.8 Hz),7.04 (1H, d, J 7.8 Hz), 5.86 (2H, s), 5.40 (2H, br s), 1.48 (6H, s);LC-MS Retention time 2.25 min; (M+H)⁺ 387.

Example 217-(3-cyanophenyl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from 7-chloro-3-(6-[1-hydroxy-1-cyclopentyl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineby the method described in Example 10.

IR v_(max) (DR)/cm⁻¹ 3323, 2967, 2232, 1732, 1595, 1507, 1436, 1234,1012 and 794; NMR δ_(H) (400 MHz, DMSO) 1.40-1.48 (2H, m), 1.55-1.81(6H, m), 4.96 (1H, s), 5.83 (2H, s), 7.04 (1H, d, J 7.5 Hz), 7.40 (2H,s), 7.55 (1H, d, J 7.0 Hz), 7.73 (1H, t, J 7.5 Hz), 7.90 (1H, t, J 8.0Hz), 8.14 (1H, dt, J 8.0, 1.5 Hz), 9.02-9.07 (2H, m); (M+H)⁺ 413.

Example 227-(3-cyanophenyl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared as described in Example 10 from7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amineand 3-cyanophenylboronic acid (0.09 g, 0.66 mmol) to give the titlecompound (28 mg, 20%) as a yellow solid.

NMR δ_(H) (400 MHz, CDCl₃) 9.06 (2H, m), 8.13 (1H, dt, J 7.8, 1.3 Hz),7.89 (1H, t, J 7.9 Hz), 7.78 (1H, t, J 7.8 Hz), 7.57 (1H, d, J 7.8 Hz),7.45 (2H br s), 7.05 (1H, d, J 7.6 Hz), 5.83 (2H, s), 5.20 (1H, s), 3.63(4H, m), 1.95 (2H, td, J 11.4, 4.5 Hz), 1.33 (1H, d, J 12.4 Hz); LC-MSRetention time 2.16 min; (M+H)⁺ 429.

Example 237-(3-cyanophenyl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand 3-cyanophenylboronic acid by the method described for Example 7 togive the title compound (0.06 g) as a white powder.

NMR δ_(H) (400 MHz, DMSO) 1.31-1.39 (1H, m), 1.60-1.66 (1H, m),2.04-2.08 (2H, m), 2.17-2.26 (2H, m), 5.62 (1H, s), 5.89 (2H, s), 7.15(1H, d, J 7.5 Hz), 7.40-7.51 (3H, m), 7.75 (1H, t, J 8.0 Hz), 7.90 (1H,t, J 7.5 Hz), 8.15 (1H, d, J 7.5 Hz), 9.04-9.12 (2H, m); (M+H)⁺ 399.

Example 24 7-(3-cyanophenyl)-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

The title compound was prepared from7-chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineand the appropriate arylboronic acid by the method described inreference example 1.

Example 25S-7-(4-methylthiazol-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

This was prepared from7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand 4-methylthiazole by the method of Example 38.

Example 267-(4-methylthiazol-2-yl)-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

This is prepared from7-chloro-3-(6-[1-hydroxy-1-methylethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineand 4-methylthiazole by the method of Example 38.

Example 277-(4-methylthiazol-2-yl)-3-(6-[1-hydroxy-1-cyclopentyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine7-Chloro-3-{6-[1-trimethylsilyloxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of7-chloro-3-{6-[1-hydroxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine(0.5 g, 1.5 mmol) in dry THF (15 mL) at room temperature was treatedwith trimethylsilyl chloride (0.38 mL, 3.0 mmol) then triethylamine(0.42 mL, 3.0 mmol); stirred at 35° C. overnight, treated withadditional quantities of trimethylsilyl chloride (0.19 mL, 1.5 mmol)then triethylamine (0.21 mL, 1.5 mmol) and stirred at 35° C. for 24 h.The mixture was poured into water (60 mL), extracted with EtOAc (×2),concentrated in vacuo and purified by chromatography(SiO₂:isohexane-EtOAc (3:1)) to give the title compound (0.55 g, 88%);NMR δ_(H) (400 MHz, DMSO) 7.78 (1H, t, J 7.8 Hz), 7.59 (2H, br s), 7.43(1H, d, J 7.8 Hz), 7.19 (1H, d, J 7.8 Hz), 5.79 (2H, s), 1.68 (7H, m),1.40 (2H, m), −0.11 (9H, s); (M+H)⁺418.

7-(4-Methylthiazol-2-yl)-3-{6-[1-trimethylsilyloxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-chloro-3-{6-[1-trimethylsilyloxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineand 4-methylthiazole by the method described for Example 30 to give thetitle compound (0.105 g, 20%); NMR δ_(H) (400 MHz, DMSO) 7.77 (1H, t, J7.9 Hz), 7.72 (1H, s), 7.44 (1H, d, J 7.9 Hz), 7.35 (2H, br s), 7.14(1H, d, J 7.4 Hz), 5.82 (2H, s), 2.56 (3H, s), 1.84 (2H, m), 1.73 (2H,m), 1.64 (2H, m), 1.40 (3H, m), −0.10 (9H, s); (M+H)⁺ 481.

7-(4-Methylthiazol-2-yl)-3-{6-[1-hydroxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of7-(4-methylthiazol-2-yl)-3-{6-[1-trimethylsilyloxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine(0.105 g, 0.22 mmol) in THF (6 mL) was treated with tetrabutylammoniumfluoride (1.0 M in THF, 0.33 mL, 0.33 mmol), refluxed for 90 min,cooled, concentrated in vacuo and partitioned between water and EtOAc.The aqueous phase was extracted with EtOAc and the combined organicphase dried (MgSO₄), concentrated in vacuo, triturated with EtOAc andthe resulting solid filtered to give the title compound (0.021 g, 24%)as a pale yellow solid.

NMR δ_(H) (400 MHz, DMSO) 1.43-1.51 (2H, m), 1.58-1.62 (2H, m),1.67-1.73 (2H, m), 1.77-1.83 (2H, m), 2.57 (3H, s), 4.97 (1H, s), 5.82(2H, s), 7.02 (1H, d, J 7.5 Hz), 7.38 (2H, b), 7.55 (1H, d, J 8.0 Hz),7.72-7.75 (2H, m); (M+H)⁺ 409.

Example 287-(4-methylthiazol-2-yl)-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

This is prepared from7chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineand 4-methylthiazole by the method of Example 38.

Example 297-(4-methylthiazol-2-yl)-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

This is prepared from7-chloro-3-(6-[1-hydroxycyclobutyl]pyrid-2-ylmethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineand 4-methylthiazole by the method of Example 38.

Example 307-(4-methylthiazol-2-yl)-3-(6-[methoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amineN-[2-Amino-4-chloro-6-({6-methoxymethyl]pyridin-2-ylmethyl}amino)pyrimidin-5-yl]formamide

Prepared from N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide(commercially available) and 6-methoxymethylpridine-2-methanamine by themethod described reference example 1.

7-Chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared fromN-[2-amino-4-chloro-6-({6-methoxymethyl]pyridin-2-ylmethyl}amino)pyrimidin-5-yl]formamideby the method described in reference example 1 to give the titlecompound; LC-MS Retention time 1.91 min, (M+H)+ 306.

3-(6-Methoxymethylpyridin-2-ylmethyl)-7-(4-methylthiazol-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of 4-methylthiazole (0.15 mL, 1.65 mmol) in dry THF (7.5 mL)was cooled to −78° C. under nitrogen, treated with n-BuLi (1.0 mL, 1.65mmol) and stirred for 30 minutes, then ZnCl (1-M, 1.65 mL, 1.65 mmol)was added, and the reaction mixture was warmed to room temperature.7-Chloro-3-(6-methoxymethylpyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine(250 mg, 0.825 mmol) was then added followed by Pd(PPh₃)₄ (48 mg, 0.04mmol) and the reaction mixture heated to reflux for 1 h. The reactionmixture was cooled to room temperature, quenched with ammonium chlorideand extracted with ethyl acetate. The organic phase was washed withwater, dried and concentrated in vacuo. The crude product was purifiedby chromatography (eluent: EtOAc-heptane 1:1 to 2:1) to give the titlecompound (38 mg, 13%) as a yellow solid.

IR v_(max) (DR)/cm⁻¹ 3324, 3302, 2921, 1651, 1596, 1519, 1418, 1366,1257, 1198 and 1112; NMR δ_(H) (400 MHz, DMSO) 7.78 (1H, t, J 7.5 Hz),7.73 (1H, s), 7.43 (2H, br s), 7.34 (1H, d, J 7.5 Hz), 7.04 (1H, d, J7.0 Hz), 5.78 (2H, s), 4.42 (2H, s), 3.33 (3H, s) and 2.56 (3H, s); LCRetention time 1.01 min (50:80); (M+H)⁺ 369.

Example 317-(5-methylfuran-2-yl)-3-(6-[difluoromethyloxymethyl]-pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine Ethyl6-difluoromethoxymethylpyridine-2-carboxylate

2,2-Difluoro-2-(fluorosulfonyl)acetic acid (495 mL, 4.79 mmol) was addeddropwise to a solution of ethyl 6-hydroxymethylpyridine-2-carboxylate(800 mg, 4.79 mmol) and CuI (91 mg, 0.479 mmol) in MeCN (10 mL) at roomtemperature at a rate to maintain the internal temperature<30° C. Themixture was stirred for a further 20 min at room temperature, pouredonto brine/water and extracted with EtOAc (×3). The combined extractswere dried (MgSO₄), filtered, evaporated and purified by columnchromatography (4:1 to 2:1, isohexane:EtOAc) to give the title compound(130 mg, 13%) as a colorless oil; NMR δ_(H) (400 MHz, CDCl₃) 8.01 (1H,d, J 7.5 Hz), 7.89 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 7.5 Hz), 6.41 (1H,t J 74.0 Hz), 5.14 (2H, s), 4.49 (2H, q, J 7.0 Hz), 1.44 (3H, t, J 7.0H); (M+H)⁺ 232.

6-Difluoromethoxymethylpyridine-2-methanol

NaBH₄ (377 mg, 9.96 mmol) was added to a solution of ethyl6-difluoromethoxymethylpyridine-2-carboxylate (2.30 g, 9.96 mmol) inEtOH (50 mL) at 0° C., the mixture was warmed to 80° C. and stirred for5 h. The mixture was cooled to 0° C., quenched with sat. aq. NH₄Cl,concentrated in vacuo and partitioned between EtOAc and brine. Theorganic layer was separated, dried (MgSO₄), filtered and evaporated togive the title compound (1.50 g, 80%) as a colorless oil; NMR δ_(H) (400MHz, CDCl₃) 7.73 (1H, t, J 8.0 Hz), 7.35 (1H, d, J 8.0 Hz), 7.19 (1H, d,J 8.0 Hz), 6.39 (1H, t, J 74.0 Hz), 5.02 (2H, s), 4.76 (2H, s); (M+H)⁺190.

2-Bromomethyl-6-difluoromethoxymethylpyridine

Prepared from 6-difluoromethoxymethylpyridine-2-methanol by thebromination method described in Example 36 to give the title compound(52%); NMR δ_(H) (400 MHz, CDCl₃) 7.74 (1H, t, J 8.0 Hz), 7.39 (1H, d, J8.0 Hz), 7.37 (1H, d, J 8.0 Hz), 6.40 (1H, t, J 74.0 Hz), 5.01 (2H, s),4.53 (2H, s); (M+H)⁺ 252, 254

3-(6-Difluoromethoxymethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and2-bromomethyl-6-difluoromethoxymethylpyridine by the alkylation methoddescribed in Example 36.

Mp: 194.8-195.1° C.; IR v_(max) (DR)/cm⁻¹ 3512, 3295, 3172, 1632, 1574,1499, 1464, 1436 and 1417; NMR δ_(H) (400 MHz, DMSO) 7.88 (1H, d, J 3.5Hz), 7.84 (1H, t, J 8.0 Hz), 7.40 (1H, d, J 8.0 Hz), 7.31 (2H, br s),7.10 (1H, d, J 8.0 Hz), 6.81 (1H, t, J 75.8 Hz), 6.52 (1H, m), 5.76 (2,s), 4.92 (2H, s), 2.46 (3H, s); (M+H)⁺ 388; Anal. Calcd forC₁₇H₁₅N₇O₂F₂: C, 52.17; H, 3.90; N, 25.30. Found: C, 52.69; H, 3.97; N,25.19.

Example 327-(5-methylfuran-2-yl)-3-(6-[2-ethoxyethoxymethyl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine3-(6-Bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and2,6-bis(bromomethyl)pyridine by the alkylation method described inExample 36; NMR δ_(H) (400 MHz, DMSO) 2.46 (3H, s), 4.64 (2H, s), 5.75(2H, s), 6.50 (1H, d, J 3.5 Hz), 7.04 (1H, d, J 8.0 Hz), 7.31 (2H, s),7.49 (1H, d, J 7.5 Hz), 7.80 (1H, t, J 7.5 Hz), 7.88 (1H, d, J 3.5 Hz).TLC (Hexane:EtOAc (1:1)) Rf=0.28**

3-(6-Ethoxyethoxymethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of 2-ethoxyethanol (242 μl, 2.5 mmol) in anhydrous THF (15mL) was cooled to 0° C. and treated with NaH (100 mg, 2.5 mmol). Thereaction was stirred at 0° C. for 10 mins, then treated with3-(6-bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine(100 mg, 0.25 mmol), stirred at room temperature for 30 mins. Thereaction was quenched with aqueous NH₄Cl and extracted with EtOAc. Thecombined organic phases were dried (MgSO₄) and concentrated in vacuo.The resulting solid was suspended in MeOH (10 mL) and treated with 4MHCl in dioxane (2 mL), the reaction mixture was then diluted withdiethyl ether (40 mL) and the resulting solid isolated by filtration togive the product (34 mg, 31%) as a yellow solid.

IR v_(max) (DR)/cm⁻¹ 3519, 3296, 3177, 2877, 1625, 1574, 1499, 1433,1322, 1228, 1112, 1023, 958 and 767; NMR δ_(H) (400 MHz, DMSO) 1.09 (3H,t, J 7.0 Hz), 2.46 (3H, s), 3.42 (2H, q, J 7.0 Hz), 3.50 (2H, dd, J 5.5Hz, 3.0 Hz), 3.58 (2H, dd, J 5.5 Hz, 4.0 Hz), 4.51 (2H, s), 5.73 (2H,s), 6.51 (1H, dd, J 3.5 Hz, 1.0 Hz), 7.03 (1H, d, J 7.5 Hz), 7.29 (2H,s), 7.36 (1H, t, J 7.5 Hz), 7.88 (1H, d, J 3.5 Hz).

Example 337-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-2-ylmethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-Bromomethyl-6-(tetrahydrofuran-2-ylmethoxymethyl)pyridine

Prepared from 2,6-bis(bromomethyl)pyridine and(RS)-tetrahydrofuran-2-methanol by the alkylation method described forthe final step of Example 32 to give the title compound (19%); NMR δ_(H)(400 MHz, CDCl₃) 7.70 (1H, t, J 7.5 Hz), 7.42 (1H, d, J 7.5 Hz), 7.33(1H, d, J 7.5 Hz), 4.73-4.65 (2H, m), 4.52 (2H, s), 4.17-4.10 (1H, m),3.93-3.87 (1H, m), 3.82-3.77 (1H, m), 3.62-3.55 (2H, m), 2.03-1.85 (3H,m), 1.71-1.62 (1H, m); (M+H)⁺ 286, 288.

(RS)-3-{6-(Tetrahydrofuran-2-ylmethoxymethyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and2-bromomethyl-6-(tetrahydrofuran-2-ylmethoxymethyl)pyridine by thealkylation method described in Example 36.

Mp: 154.2-154.5° C.; IR v_(max) (DR)/cm⁻¹ 3334, 3188, 2871, 1738, 1652,1600 and 1419; NMR δ_(H) (400 MHz, DMSO) 7.88 (1H, d, J 3.5 Hz), 7.78(1H, t, J 8.0 Hz), 7.36 (1H, d, J 8.0 Hz), 7.29 (2H, br s), 7.04 (1H, d,J 8.0 Hz), 6.53-6.51 (1H, m), 5.73 (2H, s), 4.51 2H, s), 3.98-3.93 (1H,m), 3.74-3.68 (1H, m), 3.64-3.58 (1H, m), 3.45-3.43 (2H, m), 2.46 (3H,s), 1.91-1.71 (3H, m), 1.56-1.48 (1H, m); (M+H)⁺ 422.

Example 347-(5-methylfuran-2-yl)-3-(6-[tetrahydrofuran-3-ylmethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-Bromomethyl-6-(tetrahydrofuran-3-ylmethoxymethyl)pyridine

Prepared from 2,6-bis(bromomethyl)pyridine and(RS)-tetrahydrofuran-3-methanol by the alkylation method described forthe final step of Example 32 to give the title compound (37%); NMR δ_(H)(400 MHz, CDCl₃) 7.70 (1H, t, J 8.0 Hz), 7.37-7.33 (2H, m), 4.63 (2H,s), 4.53 (2H, s), 3.89-3.82 (2H, m), 3.77-3.72 (1H, m), 3.65-3.61 (1H,m), 3.56-3.46 (1H, m), 2.66-2.56 (1H, m), 2.09-1.99 (1H, m), 1.69-1.60(1H, m); (M+H)⁺ 286, 288.

(RS)-3-{6-(Tetrahydrofuran-3-ylmethoxymethyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and2-bromomethyl-6-(tetrahydrofuran-3-ylmethoxymethyl)pyridine by thealkylation method described for Example 36.

Mp: 168.7-168.9° C.; IR v_(max) (DR)/cm⁻¹ 3514, 3293, 3171, 2935, 2860,1610, 1575, 1498 and 1434; NMR δ_(H) (400 MHz, DMSO) 7.88 (1H, d, J 3.5Hz), 7.79 (1H, t, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 7.28 (2H, br s),7.06 (1H, d, J 7.5 Hz), 6.51 (1H, dd, J 3.5, 1.0 Hz), 5.73 (2H, s), 4.49(2H, s), 3.71-3.55 (3H, m), 3.44-3.33 (3H, m), 2.51-2.41 (1H, m), 2.46(3H, s), 1.93-1.84 (1H, m), 1.54-1.45 (1H, m); (M+H)⁺ 422.

Example 357-(5-methylfuran-2-yl)-3-(6-[2-isopropyloxyethyoxy]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-Bromomethyl-6-(isopropyloxyethoxymethyl)pyridine

Prepared from 2,6-bis(bromomethyl)pyridine and 2-(isopropyloxy)ethanolby the alkylation method described for the final step of Example 32 togive the title compound (28%); NMR δ_(H) (400 MHz, CDCl₃) 7.69 (1H, t, J7.5 Hz), 7.43 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.69 (2H, s),4.53 (2H, s), 3.73-3.69 (2H, m), 3.68-3.58 (3H, m), 1.18 (6H, d, J 6.0Hz); (M+H)⁺ 288, 290.

3-{6-(Isopropyloxyethoxymethyl]pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Prepared from7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and2-bromomethyl-6-(isopropyloxyethoxymethyl)pyridine by the alkylationmethod described in Example 36.

Mp: 127.4-127.6° C.; IR v_(max) (DR)/cm⁻¹ 3484, 3326, 3210, 2968, 2869,1640, 1569, 1541, 1512, 1438 and 1416; NMR δ_(H) (400 MHz, DMSO) 7.88(1H, d, J 3.5 Hz), 7.78 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.28(2H, br s), 7.03 (1H, d, J 7.5 Hz), 6.51 (1H, dd, J 3.5, 1.0 Hz), 5.73(2H, s), 4.51 (2H, s), 3.58-3.47 (5H, m), 2.46 (3H, s), 1.06 (6H, d, J6.0 Hz); (M+H)⁺ 424.

Example 36 7-(5-methylfuran-2-yl)-3-(6-[1-methoxy-1-methylethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine2-Hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine

Methylmagnesium bromide (1.0 M in toluene/THF 3:1, 19.7 mL, 27.6 mmol)was added slowly to a stirred solution of methyl2-(hydroxymethyl)pyridine-2-carboxylate (1.0 g, 5.52 mmol) in THF (15mL) at 0° C., the mixture was allowed to warm to room temperature andstirred for 16 h. The reaction mixture was quenched with NH₄Cl aq,partitioned between EtOAc and sat aq NH₄Cl, the organic portion wasseparated, dried (MgSO₄), filtered and evaporated. This residue waspurified by column chromatography (1:1, EtOAc:isohexane) to give thetitle compound (530 mg, 58%) as a colourless oil; NMR δ_(H) (400 MHz,CDCl₃) 7.72 (1H, t, J 7.5 Hz), 7.32 (1H, d, J 7.5 Hz), 7.19 (1H, d, J7.5 Hz), 4.79 (2H, s), 4.42 (1H, br s), 3.18 (1H, br s), 1.57 (6H, s);(M+H)⁺ 168.

2-tert-Butyldimethylsilyloxymethyl-6-(1-hydroxy-1-methylethyl)pyridine

Imidazole (2.27 g, 33.3 mmol) was added to a stirred solution of2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.30 g, 31.7 mmol)and tert-butyldimethylsilylchloride (5.02 g, 33.3 mmol) in DMF (70 mL)and the mixture was stirred for 16 h at room temperature. The mixturewas poured onto water, extracted with EtOAc, the organic portion wasseparated, dried (MgSO₄), filtered and evaporated to give the titlecompound (8.19 g, 92%) as a colourless oil; NMR δ_(H) (400 MHz, CDCl₃)7.74-7.70 (1H, m), 7.40-7.38 (1H, m), 7.20-7.18 (1H, m), 5.34 (1H, s),4.83 (2H, s), 1.52 (6H, s), 0.97 (9H, s), 0.13 (6H, s); (M+H)⁺ 282.

2-tert-Butyldimethylsilyoxymethyl-6-(1-methoxy-1-methylethyl)pyridine

NaH (285 mg, 7.12 mmol) was added portionwise to a stirred solution of2-tert-butyldimethylsilyloxymethyl-6-(1-hydroxy-1-methylethyl)pyridine(2.0 g, 7.12 mmol) in DMF (30 mL) at room temperature. After 20 min,methyl iodide (1.33 mL, 21.4 mmol) was added, the mixture was warmed to50° C. and stirred for 16 h at this temperature. The mixture was pouredonto water, extracted with EtOAc (×3), the combined extracts were dried(MgSO₄), filtered evaporated and the residue purified by columnchromatography (20:1 to 10:1, isohexane:EtOAc) to give the titlecompound (1.20 g, 57%) as a colorless oil; NMR δ_(H) (400 MHz, CDCl₃)7.69-7.65 (1H, m), 7.38-7.34 (2H, m), 4.81 (2H, s), 3.15 (3H, s), 1.53(6H, s), 0.96 (9H, s), 0.12 (6H, s).

2-Hydroxymethyl-6-(1-methoxy-1-methylethyl)pyridine

A solution of2-tert-butyldimethylsilyloxymethyl-6-(1-methoxy-1-methylethyl)pyridine(1.20 g, 4.08 mmol) in AcOH (45 mL), THF (15 mL) and H₂O (15 mL) wasstirred for 48 h at room temperature. The solvent was removed in vacuo,the residue was partitioned between DCM and sat aq NaHCO₃, the organicportion was separated, dried (MgSO₄), filtered and evaporated to givethe title compound (740 mg, 100%) as a colourless oil; NMR δ_(H) (400MHz, CDCl₃) 7.70-7.66 (1H, m), 7.48-7.45 (1H, m), 7.07-7.04 (1H, m),4.74 (2H, d, J 5.0 Hz), 4.14 (1H, t, J 5.0 Hz), 3.18 (3H, s), 1.57 (6H,s).

2-Bromomethyl-6-(1-methoxy-1-methylethyl)pyridine

Carbon tetrabromide (1.59 g, 4.80 mmol) was added portionwise to astirred solution of 2-hydroxymethyl-6-(1-methoxy-1-methylethyl)pyridine(724 mg, 4.00 mmol) and triphenylphosphine (1.15 g, 4.40 mmol) in DCM(50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h thenconcentrated in vacuo. The residue was purified by column chromatography(20:1 to 5:1 isohexane:EtOAc) to give the title compound (732 mg, 75%)as a colourless oil; NMR δ_(H) (400 MHz, CDCl₃) 7.69-7.65 (1H, m),7.46-7.43 (1H, m), 7.32-7.30 (1H, m), 4.55 (2H, s), 3.17 (3H, s), 1.55(6H, s).

3-{6-(2-Methoxy-2-propyl)pyridin-2-ylmethyl}-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

NaH (100 mg, 2.50 mmol) was added portionwise to a stirred suspension oftriazole (538 mg, 2.50 mmol) in DMF (10 mL) at 0° C. After 15 min2-bromomethyl-6-(1-methoxy-1-methylethyl)pyridine (732 mg, 3.00 mmol) inDMF (3 mL) was added, the mixture was allowed to warm to roomtemperature and stirred for 16 h. The solvent was removed in vacuo, theresidue was taken up in MeOH and evaporated onto silica prior topurification by column chromatography (1:1 to 2:1 EtOAc:isohexane) togive the tide compound (280 mg, 30%) as an off-white solid.

Mp: 178.0-178.5° C.; IR v_(max) (DR)/cm⁻¹ 3469, 3317, 3175, 2982, 2932,2825, 1648, 1568, 1512 and 1436; NMR δ_(H) (400 MHz, DMSO) 7.88 (1H, d,J 3.0 Hz), 7.76 (1H, t, J 7.5 Hz), 7.41 (1H, d, J 7.5 Hz), 7.24 (2H, brs), 7.02 (1H, d, J 7.5 Hz), 6.52-6.50 (1H, m), 5.77 (2H, s), 3.01 (3H,s), 2.46 (3H, s), 1.28 (6H, s); (M+H)⁺ 380.

Example 377-(5-methylfuran-2-yl)-3-(6-[2,2,2-trifluoroethyl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

Prepared from3-(6-bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and trifluoroethanol by themethod described in Example 32.

IR v_(max) (DR)/cm⁻¹ 3282, 3098, 1954, 1649, 1520, 1463, 1282, 1165,1029 and 761; NMR δ_(H) (400 MHz, DMSO) 2.46 (3H, s), 4.14 (2H, q, J 9.0Hz), 4.68 (2H, s), 5.76 (4H, s), 6.52 (1H, d, J 3.0 Hz), 7.11 (1H, d, J7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.84 (1H, t, J7.5 Hz), 7.89 (1H, d, J3.0 Hz).

Example 38S-7-(thiazol-2-yl)-3-(6-[tetrahydrofuran-3-yl]oxymethylpyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

A solution of thiazole (0.070 g, 0.822 mmol) in dry THF (8 mL) at −78°C. was treated with n-butyllithium (2.5 M in hexanes, 0.39 mL, 0.987mmol), stirred for 20 min, treated with a solution of ZnCl₂ (0.5-M inTHF, 2.47 mL) then warmed to room temperature and stirred for 1 h. Themixture was treated with7-chloro-3-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine(0.099 g, 0.274 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.016 g, 0.014 mmol), heated at reflux for 5 h, cooled, concentrated invacuo, and purified by chromatography (SiO₂; EtOAc) to give the titlecompound (0.024 g, 21%) as a solid.

NMR δ_(H) (400 MHz, d₆-DMSO) 8.28 (1H, d, J 3.0 Hz), 8.17 (1H, d, J 3.0Hz), 7.79 (1H, t, J 8.0 Hz), 7.50 (2H, br s), 7.35 (1H, d, J 8.0 Hz),7.08 (1H, d, J 8.0 Hz), 5.78 (2H, s), 4.47 (2H, s), 4.22-4.19 (1H, m),3.75-3.60 (4H, m) and 1.99-1.88 (2H, m); LC-MS Retention time 1.89 min;(M+H)⁺ 411.

The following example does not form a part of the invention:

Reference Example 17-phenyl-3-(6-[2-oxopyrrolidin-1-yl]pyrid-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine 6-Bromopyridine-2-methanol

A solution of 6-bromopyridine-2-carbaldehyde (10.00 g, 53.76 mmol) inMeOH (120 mL) was treated with sodium borohydride (2.04 g, 53.76 mmol),stirred for 1 h and partitioned between EtOAc and water. The organicphase was separated and the aqueous re-extracted with ethyl acetate. Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto give the title compound (9.76 g, 97%) as a pale-yellow liquid; LC-MSretention time 1.52 min, (M+H)⁺ 188 and 190.

1-(6-Hydroxymethylpyridin-2-yl)pyrrolidin-2-one

A mixture of (6-bromopyridine-2-methanol (9.76 g, 51.9 mmol), copper(I)iodide (0.99 g, 5.19 mmol) N,N′-dimethylethane-1,2-diamine (1.12 mL,10.38 mmol), 1,4-dioxane (400 mL) and potassium carbonate (14.35 g,103.84 mmol) was heated at reflux for 8 h, cooled, concentrated in vacuoand partitioned between EtOAc and water. The organic phase wasseparated, the aqueous phase re-extracted with EtOAc and the combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo to givethe title compound (10.19 g, quantitative) as a pale-yellow solid; NMRδ_(H) (400 MHz, CDCl₃) 8.32 (1H, d, J 8.5 Hz), 7.69 (1H, dd, J 8.5, 7.5Hz), 6.96 (1H, dd, J 7.5, 1.5 Hz), 4.71 (2H, d, J 5.0 Hz), 4.17-4.13(2H, m), 3.50 (1H, t, J 5.0 Hz), 2.70-2.66 (2H, m), 2.19-2.11 (2H, m);(M+H)⁺ 193; LC-MS Retention time 1.46 min.

1-(6-Bromomethylpyridine-2-yl)pyrrolidin-2-one

A stirred solution of 1-(6-hydroxymethylpyridin-2-yl)pyrrolidin-2-one(10.19 g, 53.01 mmol), in dichloromethane (600 mL), was treated withtriphenylphosphine (15.29 g, 58.31 mmol) followed by carbon tetrabromide(15.66 g, 58.31 mmol), stirred for 1 h, concentrated in vacuo andpurified by column chromatography (SiO₂; EtOAc:hexane (1:1)) to give thetitle compound (10.19 g) as a white solid also containingtriphenylphosphine oxide as an impurity; NMR δ_(H) (400 MHz, d₆-DMSO)inter alia 8.22 (1 H, d, J 8.5 Hz), 7.81 (1 H, t, J 7.5 Hz), 7.28 (1H,d, J 7.5 Hz), 4.63 (2 H, s), 3.98 (2 H, t, J 7.0 Hz), 2.58 (2 H, t, J8.0 Hz) and 2.08-2.00 (2 H, m); (M+H)⁺ 255, 257.

1-(6-Azidomethylpyridin-2-yl)pyrrolidin-2-one

A solution of 1-(6-bromomethylpyridin-2-yl)pyrrolidin-2-one (10.19 g,39.94 mol) containing triphenylphosphine oxide impurity in DMF (80 mL)was treated with sodium azide (2.60 g, 39.94 mmol), stirred for 18 h andpartitioned between EtOAc and water. The organic phase was separated andthe aqueous phase re-extracted with EtOAc (×2). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give; the titlecompound as a yellow oil, contaminated with triphenylphosphine oxide;used in the next step without further purification; LC-MS retention time2.19 min, (M+H)⁺ 218.

1-(6- Aminomethylpyridin-2-yl)pyrrolidin-2-one

A solution of crude 1-(6-azidomethyl-pyridin-2-yl)pyrrolidin-2-one(containing triphenylphosphine oxide), in ethanol (100 mL) was treatedwith platinum (5% on carbon), stirred under hydrogen at 45° C. andambient pressure for 18 h, filtered through a pad of Celite,concentrated in vacuo then co-evaporated with toluene and thenchloroform to give the title compound (11.32 g) as a white solid,contaminated with triphenylphosphine oxide; LC-MS retention time 0.66min, (M+H)⁺ 192.

N-(2-Amino-4-chloro-6-{[6-(2-oxopyrrolidin-1-yl)pyridin-2-ylmethyl]amino}pyrimidin-5-yl)formamide

A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (3.61 g,17.43 mmol) and 1-(6-aminomethylpyridin-2-yl)pyrrolidin-2-one(containing triphenylphosphine oxide) (10.00 g, ca. 50 mmol) andtriethylamine (4.86 mL, 34.86 mmol) in propan-2-ol (100 mL) was heatedat reflux for 18 h, cooled and the resulting precipitate filtered togive the title compound (3.41 g) as an off-white solid; NMR δ_(H) (400MHz, d₆-DMSO) 9.21 (1 H, s), 8.20 (1 H, d, J 1 Hz), 8.12 (1 H, d, J 8.5Hz), 7.73 (1 H, t, J 7.5 Hz), 7.38 (1 H, t, J 6 Hz), 7.02 (1 H, d, J 7.5Hz), 6.45 (2 H, br s), 4.53 (2 H, d, J 6.0 Hz), 4.00-3.95 (2 H, m), 2.57(2 H, t, J 8.0 Hz) and 2.08-2.00 (2 H, m).

1-{6-[(2,5-diamino-6-chloro-pyrimidin-4-ylamino)methyl]pyridin-2-yl}pyrrolidin-2-one

A mixture of asN-(2-amino-4-chloro-6-{[6-(2-oxo-pyrrolidin-1-yl)pyridin-2-ylmethyl]amino}pyrimidin-5-yl)formamide(3.41 g, 9.43 mmol) in ethanol (36 mL) was treated with hydrochloricacid (6-M, 8 mL), heated at reflux for 2 h, cooled and the pH adjustedto 13 with aqueous sodium hydroxide (5-M). The mixture was extractedwith EtOAc (×3) and the combined organic extracts were dried (Na₂SO₄)and concentrated in vacuo to give the title compound (2.12 g, 68%) as acoral pink solid; LC-MS retention time 1.64 min; (M+H)⁺ 334.

1-[6-(5-Amino-7-chloro[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-pyridin-2-yl]-pyrrolidin-2-one

A suspension of1-{6-[(2,5-diamino-6-chloro-pyrimidin-4-ylamino)methyl]pyridin-2-yl}pyrrolidin-2-one(2.10 g, 6.29 mmol) in glacial acetic acid (6 mL) and EtOH (24 mL) at 0°C. was treated with a solution of sodium nitrite (0.564 g, 8.17 mmol) inwater (1.5 mL), stirred for 2 h, warmed to room temperature and theresulting precipitate filtered and dried to give the title compound(1.67 g, 77%) as an off-white solid; LC-MS retention time 1.99 min,(M+H)⁺ 345.

1-[6-(5-Amino-7-phenyl[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridin-2-yl]pyrrolidin-2-one

A mixture of1-[6-(5-amino-7-chloro[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridin-2-yl]pyrrolidin-2-one(0.50 g, 1.45 mmol) and phenylboronic acid (0.354 g, 2.90 mmol) insaturated aqueous sodium hydrogen carbonate (5 mL) and 1,4-dioxane (20mL) was degassed with a stream of nitrogen for 10 min then treated withtetrakis(triphenylphosphine)palladium(0) (0.083 g, 0.0725 mmol),refluxed for 2 h then partitioned between EtOAc and water. The organicphase was separated and the aqueous phase re-extracted with EtOAc (×2).The combined organic extracts were dried (MgSO₄), concentrated in vacuoto give a yellow solid (1.00 g) which was purified by columnchromatography [SiO₂; EtOAc-hexane (1:1) then EtOAc]. The resultingyellow solid (0.68 g) was triturated with diethyl ether to give thetitle compound (0.38 g, 68%) as an off-white solid.

NMR δ_(H) (400 MHz, d₆-DMSO) 8.77-8.74 (2H, m), 8.19 (1H, d, J 8.5 Hz),7.79 (1H, t, J 7.5 Hz), 7.66-7.65 (2H, m), 7.32 (2H, br s), 6.96 (1H, d,J 7.5 Hz), 5.77 (2H, s), 3.67 (2H, t, J 7 Hz) and 1.99-1.89 (2H, m);LC-MS Retention time 2.32 min; (M+H)⁺ 387.

Biological Methods

Adenosine Receptor Binding: Binding Affinities at hA₁ Receptors

The compounds were examined in an assay measuring in vitro binding tohuman adenosine A₁ receptors by determining the displacement of theadenosine A₁ receptor selective radioligand8-Cyclopentyl-1,3-dipropylxanthine ([³H]DPCPX) using standardtechniques. See, for example, Lohse M J, et al., (1987),8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)—a selective high affinityantagonist radioligand for A1 adenosine receptors. Naunyn SchmiedebergsArch Pharmacol., 336(2): 204-10, which is incorporated by reference inits entirety.

Frozen CHO-K1 cells (transfected with a human adenosine A₁ receptorexpression vector) were homogenized in 130 mL of 50 mM Tris HCl buffer(pH 7.5) containing 10 mM MgCl₂, and 0.1 IU/mL adenosine deaminase perpellet using a Ultra-Turrax homogeniser. The resultant homogenate waskept for immediate use in the binding.

Binding assays were performed in a total volume of 250 μL, containing[³H]-DPCPX (3.0 nM), membranes and additional drugs. Total binding wasdetermined using drug dilution buffer (50 mM Tris-HCl pH:7.5, 10 mMMgCl₂, 5% DMSO). Non-specific binding was determined using 300 μMN6-cyclohexyladenosine (CHA). Following incubation for 90 minutes at 21°C., assays were terminated by rapid filtration with GF/B filters(presoaked in 0.1% (w/v) polyethylenimine) using a Canberra Packardfiltermate 196, washed 3 times with ice-cold Tris-HCl (pH 7.4). Filterswere left to dry overnight, and Microscint-0 scintillation fluid wasthen added to the filters. The filters were then left for at least 2hours before the radioactivity was assessed using a Canberra PackardTopCount microplate scintillation counter.

To determine the free ligand concentration, three vials were countedwith 25 μL of [³H]DPCPX containing 4 mL of Ultima-Gold MV scintillant ona Beckman LS6500 multi-purpose scintillation counter.

Data was analysed using a 4 parameter logistical equation and non-linearregression which yields affinity constants (pIC₅₀), and slopeparameters:

$E = {{NSB} + \frac{{Total} - {NSB}}{1 + \left( \frac{\log\left\lbrack {IC}_{50} \right\rbrack}{\log\lbrack A\rbrack} \right)^{slope}}}$where E is the quantity of binding and [A] is the competitorconcentration. The K_(i) is then determined using the Cheng-Prusoffequation:

$K_{t} = \frac{{IC}_{50}}{1 + \left( \frac{\lbrack L\rbrack}{\left\lbrack K_{D} \right\rbrack} \right)}$Adenosine Receptor Binding: Binding Affinities at hA_(2A) Receptors

The compounds were examined in an assay measuring in vitro binding tohuman adenosine A_(2A) receptors by determining the displacement of theadenosine A_(2A) receptor selective radioligand4-[2-[[6-Amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoicacid hydrochloride ([³H]CGS-21680) using standard techniques. See, forexample, Jarvis et al., J Pharmacol Exp Ther., 251(3): 888-93, which isincorporated by reference in its entirety.

Frozen HEK-293 cells were homogenized in 65 mL of 50 mM Tris HCl buffer(pH 7.5) containing 10 mM MgCl₂, and 0.1 IU/mL adenosine deaminase perpellet using a Ultra-Turrax homogenizer. The resultant homogenate waskept for immediate use in the binding assay. Binding assays wereperformed in a total volume of 250 μL, containing [³H]-CGS21680 (20.0nM), membranes and additional drugs. Total binding was determined usingdrug dilution buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 5% DMSO).Non-specific binding was determined using 300 μM CHA. Followingincubation for 90 minutes at 21° C., assays were terminated by rapidfiltration with GF/B filters (presoaked in 0.1% (w/v) polyethylenimine)using a Canberra Packard filtermate 196, washed 3 times with ice-coldTris-HCl (pH 7.4). Filters were left to dry overnight, and Microscint-0scintillation fluid was then added to the filters. The filters were thenleft for at least 2 hours before the radioactivity was assessed using aCanberra Packard TopCount microplate scintillation counter.

To determine the free ligand concentration, three vials were countedwith 25 μL of [³H]CGS21680 containing 4 mL of Ultima-Gold MV scintillanton a Beckman LS6500 multi-purpose scintillation counter.

Data was analysed using a 4 parameter logistical equation and non-linearregression which yields affinity constants (pIC₅₀), and slopeparameters:

$E = {{NSB} + \frac{{Total} - {NSB}}{1 + \left( \frac{\log\left\lbrack {IC}_{50} \right\rbrack}{\log\lbrack A\rbrack} \right)^{slope}}}$where E is the quantity of binding and [A] is the competitorconcentration. The K_(i) is then determined using the Cheng-Prusoffequation:

$K_{t} = \frac{{IC}_{50}}{1 + \left( \frac{\lbrack L\rbrack}{\left\lbrack K_{D} \right\rbrack} \right)}$Adenosine Receptor Binding: Binding Affinities at hA_(2B) Receptors

The compounds were examined in an assay measuring in vitro binding tohuman adenosine A₃ receptors by determining the displacement of theadenosine A_(2B) receptor radioligand4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol([³H]-ZM241385) using standard techniques. See, for example, Ji andJacobson., Drug Design and Discovery., 16: 217-226, which isincorporated by reference in its entirety.

Frozen HEK-293 cells were homogenized in 65 mL of 50 mM Tris HCl buffer(pH 7.5) containing 10 mM MgCl₂, 10 mM EDTA, 0.1 mM Benzamidine and 0.1IU/mL adenosine deaminase per pellet using a Ultra-Turrax homogenizer.The resultant homogenate was kept for immediate use in the bindingassay.

Binding assays were performed in a total volume of 250 μL, containing[³H]-ZM 241385 (20 nM), membranes and additional drugs. Total bindingwas determined using drug dilution buffer (50 mM Tris-HCl pH7.5, 10 mMMgCl₂, 5% DMSO). Non-specific binding was determined using 10 μM ZM241385. Following incubation for 60 minutes at 21° C., assays wereterminated by rapid filtration with GF/B filters (presoaked in 0.1%(w/v) polyethylenimine) using a Canberra Packard filtermate 196, washed3 times with ice-cold Tris-HCl (pH 7.4). Filters were left to dryovernight, and Microscint-0 scintillation fluid was then added to thefilters. The filters were then left for at least 2 hours before theradioactivity was assessed using a Canberra Packard TopCount microplatescintillation counter.

To determine the free ligand concentration, three vials were countedwith 25 μL of [³H]-ZM 241385 containing 4 mL of Ultima-Gold MVscintillant on a Beckman LS6500 multi-purpose scintillation counter.

Data was analysed using a 4 parameter logistical equation and non-linearregression which yields affinity constants (pIC₅₀), and slopeparameters:

$E = {{NSB} + \frac{{Total} - {NSB}}{1 + \left( \frac{\log\left\lbrack {IC}_{50} \right\rbrack}{\log\lbrack A\rbrack} \right)^{slope}}}$where E is the quantity of binding and [A] is the competitorconcentration. The K_(i) is then determined using the Cheng-Prusoffequation

$K_{t} = \frac{{IC}_{50}}{1 + \left( \frac{\lbrack L\rbrack}{\left\lbrack K_{D} \right\rbrack} \right)}$Adenosine Receptor Binding: Binding Affinities at hA₃ Receptors

The compounds were examined in an assay measuring in vitro binding tohuman adenosine A₃ receptors by determining the displacement of theadenosine A₃ receptor selective radioligand4-aminobenzyl-5′-N-methylcarboxamidoadenosine ([¹²⁵I]-AB MECA) usingstandard techniques. See, for example, Olah et al., Mol Pharmacol.,45(5): 978-82, which is incorporated by reference in its entirety.

Frozen CHO-K1 cells were homogenized in 45 mL of 50 mM Tris HCl buffer(pH 7.5) containing 10 mM MgCl₂, 1 mM EDTA and 0.1IU/mL adenosinedeaminase per pellet using a Ultra-Turrax homogenizer. The resultanthomogenate was kept for immediate use in the binding assay.

Binding assays were performed in a total volume of 250 μL, containing[¹²⁵I]-AB MECA (0.04-0.08 nM), membranes and additional drugs. Totalbinding was determined using drug dilution buffer (50 mM Tris-HCl pH7.5, 10 mM MgCl₂, 5% DMSO). Non-specific binding was determined using 10μM IB-MECA. Following incubation for 60 minutes at 21° C., assays wereterminated by rapid filtration with GF/B filters (presoaked in 0.1%(w/v) polyethylenimine) using a Canberra Packard filtermate 196, washed3 times with ice-cold Tris-HCl (pH 7.4). Filters were left to dryovernight, and Microscint-0 scintillation fluid was then added to thefilters. The filters were then left for at least 2 hours before theradioactivity was assessed using a Canberra Packard TopCount microplatescintillation counter.

To determine the free ligand concentration, three vials were countedwith 25 μL of [¹²⁵I]-AB MECA containing 4 mL of Ultima-Gold MVscintillant on a Beckman LS6500 multi-purpose scintillation counter.

Data was analysed using a 4 parameter logistical equation and non-linearregression which yields affinity constants (pIC₅₀), and slopeparameters:

$E = {{NSB} + \frac{{Total} - {NSB}}{1 + \left( \frac{\log\left\lbrack {IC}_{50} \right\rbrack}{\log\lbrack A\rbrack} \right)^{slope}}}$where E is the quantity of binding and [A] is the competitorconcentration. The K_(i) is then determined using the Cheng-Prusoffequation:

$K_{t} = \frac{{IC}_{50}}{1 + \left( \frac{\lbrack L\rbrack}{\left\lbrack K_{D} \right\rbrack} \right)}$Using the assays described above, binding data were collected for anumber of the exemplified compounds of the present invention. These dataare shown in Table 1, below.

TABLE 1 Binding Affinity Binding Selectivity Example hA1- hA2A- hA2B-hA3- A2b/ A3/ no. Ki Ki Ki Ki A1/A2a A2a A2a 1 192 3.4 3975 2498 56 1157727 (S isomer) 1 143 3.4 5513 2516 42 1605 733 (R isomer) 2 360.3 1.92192.3 706.3 192 1165 375 3 366.2 1.6 976.2 754.1 226 602 465 4 196.53.1 1134.3 1635.1 63 366 528 5 852.6 4.3 4199.7 8521.5 199 980 1989 6354.1 1.1 1373.4 1498.2 313 1216 1326 7 731.2 13.4 1244.7 8522.8 54 93634 8 214.3 4.8 1299.2 3762.2 44 269 780 9 706.1 9.8 3405.9 NT 72 347 NT11 319.9 5.2 3265.6 4304.6 62 634 836 12 270.2 2.8 1000.3 8173.7 96 3542893 14 498.4 6.0 437.1 612.9 83 73 102 17 385.7 9.9 4688.7 1947.4 39472 196 20 731.2 13.4 1244.7 8522.8 54 93 634 21 2389.1 23.9 2047.7 NT100 86 NT 23 1333.3 14.8 6821.6 NT 90 462 NT 27 1729.3 11.3 5741.27523.2 154 510 668 30 798.6 4.8 2373.4 4599.9 168 498 965 32 333.7 4.62022.4 2495.9 73 442 545 33 298.9 7.2 1975.7 2178.5 42 274 303 34 164.44.1 1893.9 2123.5 40 457 513 35 357.2 4.5 3452.9 2396.4 79 761 528 36421.6 4.5 NT 939.3 93 NT 208 37 231.2 4.4 2383.9 2489.3 52 536 560 382089.3 28.4 2979.8 NT 73 105 NT NT = not tested.For comparative purposes, several known adenosine A_(2A) antagoniststhat are described in International Patent Application Publication WO02/055083 were also tested. The results obtained are shown in Table 2,below.

TABLE 2 WO 02/055083 Binding Affinity Binding Selectivity Example hA1-hA2A- hA2B- hA3- A1/ A3/ no. Ki Ki Ki Ki A2a A2b/A2a A2a 151 101.5 5.3276.3 830.8 19 52 156 183 84.1 1.3 231.0 655.6 67 183 519 213 584.5 2.7270.7 1695.3 216 100 625 217 153.1 2.9 381.7 475.5 53 131 163 247 276.03.0 453.8 1461.2 92 151 487 Example 151 =3-(3-aminobenzyl)-7-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine.Example 183 =3-(6-methoxymethyl-2-pyridylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine.Example 213 =7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-aminehydrochloride. Example 217 =7-(2-furyl)-3-(6-isobutyloxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine.Example 247 =7-(2-furyl)-3-(6-isopropoxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine.Evaluation of Potential Anti-Parkinsonian Activity In Vivo:Haloperidol-Induced Hypolocomotion Model

It has previously been demonstrated that adenosine antagonists, such astheophylline, can reverse the behavioral depressant effects of dopamineantagonists, such as haloperidol, in rodents (see, for example, MandhaneS. N. et al., Adenosine A₂ receptors modulate haloperidol-inducedcatalepsy in rats. Eur. J. Pharmacol. 1997, 328, 135-141, which isincorporated by reference in its entirety). This approach is alsoconsidered a valid method for screening drugs with potentialantiparkinsonian effects. Thus, the ability of novel adenosineantagonists to block haloperidol-induced deficits in locomotor activityin mice can be used to assess both in vivo and potentialantiparkinsonian efficacy.

Female TO mice (25-30 g) are used for all experiments. Animals arehoused in groups of 8 (cage size-40 cm (width) by 40 cm (length) by 20cm (height)) under 12 hour light/dark cycle (lights on 08:00), in atemperature (20±2° C.) and humidity (55±15%) controlled environment.Animals have free access to food and water, and are allowed at least 7days to acclimatize after delivery before experimental use.

Liquid injectable haloperidol (e.g., 1 mL Serenance ampoules from BakerNorton, Harlow, Essex, each containing haloperidol BP 5 mg) are dilutedto a final concentration of 0.02 mg/mL using saline. Test compounds aretypically prepared as aqueous suspensions in 8% Tween. All compounds areadministered intraperitoneally in a volume of 10 mL/kg.

1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, adose that reduces baseline locomotor activity by at least 50%. Testsubstances are typically administered 5-60 minutes prior to testing. Theanimals are then placed individually into clean, clear polycarbonatecages (20 cm (width) by 40 cm (length) by 20 cm (height), with a flatperforated, Perspex lid). Horizontal locomotor activity is determined byplacing the cages within a frame containing a 3 by 6 array of photocellslinked to a computer, which tabulates beam breaks. Mice are leftundisturbed to explore for 1 hour, and the number of beams breaks madeduring this period serves as a record of locomotor activity which iscompared with data for control animals for statistically significantdifferences.

A number of the exemplified compounds of the present invention weretested in this assay and the results obtained are shown in Table 3,below.

TABLE 3 In Vivo activity HaloLMA MED Example no. (mg/kg) 1 0.3 2 1 3 1 43 5 3 6 1 8 3 9 10 12 10 14 30 18 <30 20 3 24 10 25 3 27 10 30 3 31 1 321 33 3 34 1 36 1-3 37 1 38 10Evaluation of Potential Anti-Parkinsonian Activity In Vivo: 6-OHDA Model

Parkinson's disease is a progressive neurodegenerative disordercharacterized by symptoms of muscle rigidity, tremor, paucity ofmovement (hypokinesia), and postural instability. It has beenestablished for some time that the primary deficit in PD is a loss ofdopaminergic neurons in the substantia nigra which project to thestriatum, and indeed a substantial proportion of striatal dopamine islost (ca 80-85%) before symptoms are observed. The loss of striataldopamine results in abnormal activity of the basal ganglia, a series ofnuclei which regulate smooth and well coordinated movement (see, e.g.,Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol.1996, 12, 73-94, which is incorporated by reference in its entirety).The neurochemical deficits seen in Parkinson's disease can be reproducedby local injection of the dopaminergic neurotoxin 6-hydroxydopamine intobrain regions containing either the cell bodies or axonal fibers of thenigrostriatal neurons.

By unilaterally lesioning the nigrostriatal pathway on only one-side ofthe brain, a behavioral asymmetry in movement inhibition is observed.Although unilaterally-lesioned animals are still mobile and capable ofself maintenance, the remaining dopamine-sensitive neurons on thelesioned side become supersenstive to stimulation. This is demonstratedby the observation that following systemic administration of dopamineagonists, such as apomorphine, animals show a pronounced rotation in adirection contralateral to the side of lesioning. The ability ofcompounds to induce contralateral rotations in 6-OHDA lesioned rats hasproven to be a sensitive model to predict drug efficacy in the treatmentof Parkinson's Disease.

Male Sprague-Dawley rats, obtained from Charles River, are used for allexperiments. Animals are housed in groups of 5 under 12 hour light/darkcycle (lights on 08:00), in a temperature (20±2° C.) and humidity(55±5%) controlled environment. Animals have free access to food andwater, and are allowed at least 7 days to acclimatize after deliverybefore experimental use.

Ascorbic acid, desipramine, 6-OHDA and apomorphine are obtainedcommercially. 6-OHDA is freshly prepared as a solution in 0.2% ascorbateat a concentration of 4 mg/mL prior to surgery. Desipramine is dissolvedin warm saline, and administered in a volume of 1 mL/kg. Apomorphine isdissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg.Test compounds are suspended in 8% Tween and injected in a volume of 2mL/kg.

15 minutes prior to surgery, animals are given an intraperitonealinjection of the noradrenergic uptake inhibitor desipramine (25 mg/kg)to prevent damage to nondopamine neurons. Animals are then placed in ananaesthetic chamber, and anaesthetised using a mixture of oxygen andisoflurane. Once unconscious, the animals are transferred to astereotaxic frame, where anaesthesia is maintained through a mask. Thetop of the animal's head is shaved and sterilized using an iodinesolution. Once dry, a 2 cm long incision is made along the midline ofthe scalp and the skin retracted and clipped back to expose the skull. Asmall hole is then drilled through the skull above the injection site.In order to lesion the nigrostriatal pathway, the injection cannula isslowly lowered to position above the right medial forebrain bundle at−3.2 mm anterior posterior, −1.5 mm medial lateral from bregma, and to adepth of 7.2 mm below the duramater. 2 minutes after lowing the cannula,2 VAL of 6-OHDA is infused at a rate of 0.5 μL/min over 4 minutes,yielding a final dose of 8 μg. The cannula is then left in place for afurther 5 minutes to facilitate diffusion before being slowly withdrawn.The skin is then sutured shut using Ethicon W501 Mersilk, and the animalremoved from the strereotaxic frame and returned to its homecage. Therats are allowed 2 weeks to recover from surgery before behavioraltesting.

Rotational behavior is measured using an eight station rotameter system,such as one sold by Med Associates, San Diego, USA. Each station iscomprised of a stainless steel bowl (45 cm diameter by 15 cm high)enclosed in a transparent Plexiglas cover running around the edge of thebowl, and extending to a height of 29 cm. To assess rotation, rats areplaced in cloth jacket attached to a spring tether connected to opticalrotameter positioned above the bowl, which assesses movement to the leftor right either as partial (45°) or full (360°) rotations. All eightstations are interfaced to a computer that tabulated data.

To reduce stress during drug testing, rats are initially habituated tothe apparatus for 15 minutes on four consecutive days. On the test day,rats are given an intraperitoneal injection of test compound 30 minutesprior to testing. Immediately prior to testing, animals are given asubcutaneous injection of a subthreshold dose of apomorphine, thenplaced in the harness and the number of rotations recorded for one hour.The total number of full contralatral rotations during the hour testperiod serves as an index of antiparkinsonian drug efficacy.

The invention claimed is:
 1. A compound of formula

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R is —(CR^(a)R^(b))—O—R²; R^(a) is H or alkyl; R^(b) isH or alkyl; or R^(a) and R^(b) together with the atom to which they areattached form a 3 to 8 membered saturated or partially saturatedhydrocarbon ring or form a 4 to 8 membered saturated or partiallysaturated heterocylic ring comprising a ring member selected from O,N(R³) and S; R² is H, alkyl, cycloalkyl or heterocycloalkyl, wherein thealkyl or cycloalkyl may optionally be substituted with halo, alkoxy orheterocycloalkyl; and R³ is H or alkyl; wherein: heteroaryl is a 5 or 6membered aromatic ring, comprising one or two ring members selected fromN, N(R⁴), S and O; alkyl (or the alkyl group of the alkoxy group) is alinear or branched saturated hydrocarbon containing up to 10 carbonatoms; heterocycloalkyl is a Clinked or N-linked 3 to 10 memberednon-aromatic, monocyclic ring, wherein the heterocycloalkyl ringcomprises 1, 2 or 3 ring members independently selected from N, N(R⁴),S(O)_(q) and O; R⁴ is H or alkyl; and q is 0, 1 or
 2. 2. The compound ofclaim 1, wherein R^(a) and R^(b) are independently H; and R² istetrahydrofuranyl.
 3. The compound of claim 1, wherein R^(a) and R^(b)are independently H.
 4. The compound of claim 1, wherein R is